%% This BibTeX bibliography file was created using BibDesk. %% http://www.cs.ucsd.edu/~mmccrack/bibdesk.html %% Created for Luis Vazquez at 2004-05-24 11:02:44 -0700 @article{Schuman1999, Author = {E. M. Schuman}, Journal = {Neuron}, Month = {Aug}, Number = {4}, Pages = {645-648}, Title = {{mRNA trafficking and local protein synthesis at the synapse.}}, Volume = {23}, Year = {1999}} @article{Nakayama2000, Annote = {The shape of dendritic trees and the density of dendritic spines can undergo significant changes during the life of a neuron. We report here the function of the small GTPases Rac and Rho in the maintenance of dendritic structures. Maturing pyramidal neurons in rat hippocampal slice culture were biolistically transfected with dominant GTPase mutants. We found that expression of dominant-negative Rac1 results in a progressive elimination of dendritic spines, whereas hyperactivation of RhoA causes a drastic simplification of dendritic branch patterns that is dependent on the activity of a downstream kinase ROCK. Our results suggest that Rac and Rho play distinct functions in regulating dendritic spines and branches and are vital for the maintenance and reorganization of dendritic structures in maturing neurons.}, Author = {A. Y. Nakayama and M. B. Harms and L. Luo}, Journal = {J Neurosci}, Month = {Jul}, Number = {14}, Pages = {5329-38}, Title = {{Small GTPases Rac and Rho in the maintenance of dendritic spines and branches in hippocampal pyramidal neurons.}}, Volume = {20}, Year = {2000}} @article{Matus1982, Annote = {Antibodies against actin were used to corroborate the presence of actin as a major component protein of isolated brain postsynaptic densities. The same antibodies also were used as an immunohistochemical stain to study the distribution of actin in sections of intact brain tissue. This showed two major sites where actin is concentrated: smooth muscle cells around blood vessels and postsynaptic sites. In the postsynaptic area the highest concentration of actin occurs in postsynaptic densities and there also is intense staining in the surrounding cytoplasm, especially within dendritic spines. Antiactin staining was much weaker in other parts of neurons and in glial cells. The high concentration of actin in dendritic spines may be related to shape changes that these structures have been found to undergo in response to prolonged afferent stimulation.}, Author = {A. Matus and M. Ackermann and G. Pehling and H. R. Byers and K. Fujiwara}, Journal = {Proc Natl Acad Sci U S A}, Month = {Dec}, Number = {23}, Pages = {7590-7594}, Title = {{High actin concentrations in brain dendritic spines and postsynaptic densities.}}, Volume = {79}, Year = {1982}} @article{Meng2002, Annote = {In vitro studies indicate a role for the LIM kinase family in the regulation of cofilin phosphorylation and actin dynamics. In addition, abnormal expression of LIMK-1 is associated with Williams syndrome, a mental disorder with profound deficits in visuospatial cognition. However, the in vivo function of this family of kinases remains elusive. Using LIMK-1 knockout mice, we demonstrate a significant role for LIMK-1 in vivo in regulating cofilin and the actin cytoskeleton. Furthermore, we show that the knockout mice exhibited significant abnormalities in spine morphology and in synaptic function, including enhanced hippocampal long-term potentiation. The knockout mice also showed altered fear responses and spatial learning. These results indicate that LIMK-1 plays a critical role in dendritic spine morphogenesis and brain function.}, Author = {Y. Meng and Y. Zhang and V. Tregoubov and C. Janus and L. Cruz and M. Jackson and W. Y. Lu and J. F. MacDonald and J. Y. Wang and D. L. Falls and Z. Jia}, Journal = {Neuron}, Month = {Jul}, Number = {1}, Pages = {121-33}, Title = {{Abnormal spine morphology and enhanced LTP in LIMK-1 knockout mice.}}, Volume = {35}, Year = {2002}} @article{Ishikawa2003, Annote = {Rho family of small GTPases are key regulators for morphological changes of neurons on the basis of reorganization of the actin cytoskeleton. Rnd1, a novel member of this family, is predominantly expressed in neurons in brain; however, the neuronal functions of Rnd1 are not known. Here we investigated the effect of Rnd1 on neuronal morphology. Northern blot analysis of Rnd1 expression in rat brain showed that Rnd1 mRNA was highly expressed during early postnatal period, the synaptogenic stage. In situ hybridization analysis at this period revealed that Rnd1 mRNA was strongly expressed in neurons, including the hippocampal pyramidal neurons. Furthermore, immunoblot analysis showed that Rnd1 protein was localized in synaptosomal membrane fraction. Ectopical overexpression of Rnd1 in cultured rat hippocampal neurons promoted the elongation of dendritic spines. On the other hand, suppression of endogenous Rnd1 level by antisense oligonucleotide of Rnd1 caused the increase in the percentage of headless protrusions accompanied by the reduction in the spine number and spine width and shortened the length of the headless protrusions. These results indicate that Rnd1 plays a role in spine formation in the developmental synaptogenic stage.}, Author = {Y. Ishikawa and H. Katoh and M. Negishi}, Journal = {J Neurosci}, Month = {Dec}, Number = {35}, Pages = {11065-72}, Title = {{A role of Rnd1 GTPase in dendritic spine formation in hippocampal neurons.}}, Volume = {23}, Year = {2003}} @article{Ma2003, Annote = {The structures of dendritic spines and the dendritic tree, key determinants of neuronal function, are regulated by diverse inputs that affect many scaffolding and signaling molecules. Nevertheless, here we show that reduced expression of a single gene results in loss of dendritic spines and a decrease in dendritic complexity. Kalirin, a dual Rho GDP-GTP exchange factor, causes spine formation when overexpressed. Reduced expression of Kalirin in CA1 hippocampal neurons resulted in a reduction in linear spine density, with dispersion of postsynaptic density markers and elimination of presynaptic endings. Simplification of the apical dendritic tree preceded simplification of basal dendrites. Pyramidal cell axons were not dramatically altered. Although many factors determine dendrite shape and spine formation, expression of Kalirin is necessary for the normal function of these many regulatory elements.}, Author = {X. M. Ma and J. Huang and Y. Wang and B. A. Eipper and R. E. Mains}, Journal = {J Neurosci}, Month = {Nov}, Number = {33}, Pages = {10593-603}, Title = {{Kalirin, a multifunctional Rho guanine nucleotide exchange factor, is necessary for maintenance of hippocampal pyramidal neuron dendrites and dendritic spines.}}, Volume = {23}, Year = {2003}} @article{Petralia1999, Annote = {Early in postnatal development, glutamatergic synapses transmit primarily through NMDA receptors. As development progresses, synapses acquire AMPA receptor function. The molecular basis of these physiological observations is not known. Here we examined single excitatory synapses with immunogold electron-microscopic analysis of AMPA and NMDA receptors along with electrophysiological measurements. Early in postnatal development, a significant fraction of excitatory synapses had NMDA receptors and lacked AMPA receptors. As development progressed, synapses acquired AMPA receptors with little change in NMDA receptor number. Thus, synapses with NMDA receptors but no AMPA receptors can account for the electrophysiologically observed 'silent synapse'.}, Author = {R. S. Petralia and J. A. Esteban and Y. X. Wang and J. G. Partridge and H. M. Zhao and R. J. Wenthold and R. Malinow}, Journal = {Nat Neurosci}, Month = {Jan}, Number = {1}, Pages = {31-36}, Title = {{Selective acquisition of AMPA receptors over postnatal development suggests a molecular basis for silent synapses.}}, Volume = {2}, Year = {1999}} @article{Fifkova1982, Annote = {We have demonstrated that, after permeation with saponin and decoration with S-1 myosin subfragment, the cytoplasmic actin is organized in filaments in dendritic spines, dendrites, and axon terminals of the dentate molecular layer. The filaments are associated with the plasma membrane and the postsynaptic density with their barbed ends and also in parallel with periodical cross bridges. In the spine stalks and dendrites, the actin filaments are organized in long strands. Given the contractile properties of actin, these results suggest that the cytoplasmic actin may be involved in various forms of experimentally induced synaptic plasticity by changing the shape or volume of the pre- and postsynaptic side and by retracting and sprouting synapses.}, Author = {E. Fifkova and R. J. Delay}, Journal = {J Cell Biol}, Month = {Oct}, Number = {1}, Pages = {345-50}, Title = {{Cytoplasmic actin in neuronal processes as a possible mediator of synaptic plasticity.}}, Volume = {95}, Year = {1982}} @article{Passafaro2001, Annote = {Using a thrombin cleavage assay in cultured hippocampal neurons, we studied the kinetics, regulation and site of AMPA receptor surface delivery. Surface insertion of the GluR1 subunit occurs slowly in basal conditions and is stimulated by NMDA receptor activation and insulin, whereas GluR2 exocytosis is constitutively rapid. Although both subunits ultimately concentrate in synapses, GluR1 and GluR2 show different spatial patterns of surface accumulation, consistent with GluR1 being inserted initially at extrasynaptic sites and GluR2 being inserted more directly at synapses. The spatiotemporal pattern of surface accumulation is determined by the cytoplasmic tails of GluR subunits, and in heteromeric receptors, GluR1 acts dominantly over GluR2. We propose that GluR1 controls the exocytosis and GluR2/3, the recycling and endocytosis of AMPA receptors.}, Author = {M. Passafaro and V. Piech and M. Sheng}, Journal = {Nat Neurosci}, Month = {Sep}, Number = {9}, Pages = {917-26}, Title = {{Subunit-specific temporal and spatial patterns of AMPA receptor exocytosis in hippocampal neurons.}}, Volume = {4}, Year = {2001}} @article{Lin2000, Annote = {Internalization of postsynaptic AMPA receptors depresses excitatory transmission, but the underlying dynamics and mechanisms of this process are unclear. Using immunofluorescence and surface biotinylation, we characterized and quantified basal and regulated AMPA receptor endocytosis in cultured hippocampal neurons, in response to synaptic activity, AMPA and insulin. AMPA-induced AMPA receptor internalization is mediated in part by secondary activation of voltage-dependent calcium channels, and in part by ligand binding independent of receptor activation. Although both require dynamin, insulin- and AMPA-induced AMPA receptor internalization are differentially dependent on protein phosphatases and sequence determinants within the cytoplasmic tails of GluR1 and GluR2 subunits. AMPA receptors internalized in response to AMPA stimulation enter a recycling endosome system, whereas those internalized in response to insulin diverge into a distinct compartment. Thus, the molecular mechanisms and intracellular sorting of AMPA receptors are diverse, and depend on the internalizing stimulus.}, Author = {J. W. Lin and W. Ju and K. Foster and S. H. Lee and G. Ahmadian and M. Wyszynski and Y. T. Wang and M. Sheng}, Journal = {Nat Neurosci}, Month = {Dec}, Number = {12}, Pages = {1282-90}, Title = {{Distinct molecular mechanisms and divergent endocytotic pathways of AMPA receptor internalization.}}, Volume = {3}, Year = {2000}} @article{Durand1996, Annote = {Long-term potentiation (LTP) is a cellular mechanism that potentially underlies learning and memory. To test the hypothesis that LTP is involved in activity-dependent synapse formation, we combined whole-cell recordings and confocal microscopy to investigate hippocampal glutamatergic synapses at their earliest stages of development. Here we report that, during the first postnatal week, the hippocampal glutamatergic network becomes gradually functional owing to the transformation of precursor, pure NMDA (N-methyl-D-aspartate)-receptor-based synaptic contacts into conducting AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionate)/NMDA-re cep tor-type synapses. This functional synapse induction is caused by an associative form of LTP, so it is input-specific and easily triggered experimentally by pairing presynaptic stimulation with postsynaptic depolarization. Our results challenge previous views that LTP occurs in the hippocampus only at later stages of development and that its induction requires dendritic spines. They also provide direct evidence that LTP is important for the activity-dependent formation of conducting glutamatergic synapses in the developing mammalian brain.}, Author = {G. M. Durand and Y. Kovalchuk and A. Konnerth}, Journal = {Nature}, Month = {May}, Number = {6577}, Pages = {71-75}, Title = {{Long-term potentiation and functional synapse induction in developing hippocampus.}}, Volume = {381}, Year = {1996}} @article{Isaac1995, Annote = {Recent work has suggested that some proportion of excitatory synapses on hippocampal CA1 pyramidal cells that express NMDA receptors (NMDARs) may not express functional AMPA receptors (AMPARs), thus making these synapses silent at the resting membrane potential. In agreement with this hypothesis, we demonstrate here that it is possible to stimulate synapses that yield no detectable excitatory postsynaptic currents (EPSCs) when the cell is held at -60 mV; yet at positive holding potentials (+30 to +60 mV), EPSCs can be elicited that are completely blocked by the NMDAR antagonist, D-APV. When these functionally silent synapses are subjected to an LTP induction protocol, EPSCs mediated by AMPARs appear and remain for the duration of the experiment. This conversion of silent synapses to functional synapses is blocked by D-APV. These results suggest that LTP may involve modification of AMPARs that, prior to LTP, were either not present in the postsynaptic membrane or electrophysiologically silent. This mechanism may account for several experimental results previously attributed to presynaptic changes in quantal content.}, Author = {J. T. Isaac and R. A. Nicoll and R. C. Malenka}, Journal = {Neuron}, Month = {Aug}, Number = {2}, Pages = {427-34}, Title = {{Evidence for silent synapses: implications for the expression of LTP.}}, Volume = {15}, Year = {1995}} @article{Liao1995, Annote = {Long-term potentiation (LTP) is an enhancement of synaptic strength that can be produced by pairing of presynaptic activity with postsynaptic depolarization. LTP in the hippocampus has been extensively studied as a cellular model of learning and memory, but the nature of the underlying synaptic modification remains elusive, partly because our knowledge of central synapses is still limited. One proposal is that the modification is postsynaptic, and that synapses expressing only NMDA (N-methyl-D-aspartate) receptors before potentiation are induced by LTP to express functional AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate) receptors. Here we report that a high proportion of synapses in hippocampal area CA1 transmit with NMDA receptors but not AMPA receptors, making these synapses effectively non-functional at normal resting potentials. These silent synapses acquire AMPA-type responses following LTP induction. Our findings challenge the view that LTP in CA1 involves a presynaptic modification, and suggest instead a simple postsynaptic mechanism for both induction and expression of LTP.}, Author = {D. Liao and N. A. Hessler and R. Malinow}, Journal = {Nature}, Month = {Jun}, Number = {6530}, Pages = {400-404}, Title = {{Activation of postsynaptically silent synapses during pairing-induced LTP in CA1 region of hippocampal slice.}}, Volume = {375}, Year = {1995}} @article{Heynen2000, Annote = {Experience-dependent regulation of synaptic strength has been suggested as a physiological mechanism by which memory storage occurs in the brain. Although modifications in postsynaptic glutamate receptor levels have long been hypothesized to be a molecular basis for long-lasting regulation of synaptic strength, direct evidence obtained in the intact brain has been lacking. Here we show that in the adult brain in vivo, synaptic glutamate receptor trafficking is bidirectionally, and reversibly, modified by NMDA receptor-dependent synaptic plasticity and that changes in glutamate receptor protein levels accurately predict changes in synaptic strength. These findings support the idea that memories can be encoded by the precise experience-dependent assignment of glutamate receptors to synapses in the brain.}, Author = {A. J. Heynen and E. M. Quinlan and D. C. Bae and M. F. Bear}, Journal = {Neuron}, Month = {Nov}, Number = {2}, Pages = {527-36}, Title = {{Bidirectional, activity-dependent regulation of glutamate receptors in the adult hippocampus in vivo.}}, Volume = {28}, Year = {2000}} @article{Petralia1992, Annote = {Since four AMPA-type excitatory amino acid receptor subunits have been cloned recently, it is now possible to localize these important molecules in the nervous system. A comprehensive study of AMPA receptor immunocytochemistry was carried out on vibratome sections of rat brain, which were immunolabeled with antibodies made against peptides corresponding to the C-terminal portions of AMPA-receptor subunits: GluR1, GluR2/3, and GluR4. Labeling was most prominent in forebrain structures such as the olfactory bulb and tubercle, septal nuclei, amygdaloid complex, hippocampus, induseum griseum, habenula, and interpeduncular nucleus, and in the cerebellum. Different patterns of immunolabeling were evident with the antibodies to the four subunits, with marked contrast between densely and lightly stained structures with antibody to GluR1, widespread dense staining with antibody to GluR2/3, and moderate staining with antibody to GluR4. In the parietal cortex, some non-pyramidal neurons were more densely stained than pyramidal cells with antibodies to GluR1. Neurons of the main olfactory bulb, other than granule cells, were most densely stained with antibody to GluR1. In the cerebellum, Bergmann glia were densely stained with antibodies to GluR1 and 4, while neurons, other than granule cells, were most densely stained with antibody to GluR2/3. Immunolabeling patterns of all antibodies were consistent with that of previous in situ hybridization histochemistry studies and with the overall pattern of 3H-AMPA binding. Electron microscopy of thin sections taken from immunolabeled vibratome sections of hippocampus and cerebral cortex showed staining which was restricted mainly to postsynaptic densities and adjacent dendritoplasm, and to neuron cell body cytoplasm. We saw no convincing examples of stained presynaptic terminals, and only limited evidence of glial staining, excepting Bergmann glia.}, Author = {R. S. Petralia and R. J. Wenthold}, Journal = {J Comp Neurol}, Month = {Apr}, Number = {3}, Pages = {329-54}, Title = {{Light and electron immunocytochemical localization of AMPA-selective glutamate receptors in the rat brain.}}, Volume = {318}, Year = {1992}} @article{Sanes2001, Author = {J. R. Sanes and J. W. Lichtman}, Journal = {Nat Rev Neurosci}, Month = {Nov}, Number = {11}, Pages = {791-805}, Title = {{Induction, assembly, maturation and maintenance of a postsynaptic apparatus.}}, Volume = {2}, Year = {2001}} @article{Watt2000, Annote = {AMPA and NMDA receptors are coexpressed at many central synapses, but the factors that control the ratio of these two receptors are not well understood. We recorded mixed miniature or evoked synaptic currents arising from coactivation of AMPA and NMDA receptors and found that long-lasting changes in activity scaled both currents up and down proportionally through changes in the number of postsynaptic receptors. The ratio of NMDA to AMPA current was similar at different synapses onto the same neuron, and this relationship was preserved following activity-dependent synaptic scaling. These data show that AMPA and NMDA receptors are tightly coregulated by activity at synapses at which they are both expressed and suggest that a mechanism exists to actively maintain a constant receptor ratio across a neuron's synapses.}, Author = {A. J. Watt and M. C. van Rossum and K. M. MacLeod and S. B. Nelson and G. G. Turrigiano}, Journal = {Neuron}, Month = {Jun}, Number = {3}, Pages = {659-70}, Title = {{Activity coregulates quantal AMPA and NMDA currents at neocortical synapses.}}, Volume = {26}, Year = {2000}} @article{Turrigiano2000, Annote = {The positive-feedback nature of Hebbian plasticity can destabilize the properties of neuronal networks. Recent work has demonstrated that this destabilizing influence is counteracted by a number of homeostatic plasticity mechanisms that stabilize neuronal activity. Such mechanisms include global changes in synaptic strengths, changes in neuronal excitability, and the regulation of synapse number. These recent studies suggest that Hebbian and homeostatic plasticity often target the same molecular substrates, and have opposing effects on synaptic or neuronal properties. These advances significantly broaden our framework for understanding the effects of activity on synaptic function and neuronal excitability.}, Author = {G. G. Turrigiano and S. B. Nelson}, Journal = {Curr Opin Neurobiol}, Month = {Jun}, Number = {3}, Pages = {358-64}, Title = {{Hebb and homeostasis in neuronal plasticity.}}, Volume = {10}, Year = {2000}} @article{Turrigiano2004, Author = {G. G. Turrigiano and S. B. Nelson}, Journal = {Nat Rev Neurosci}, Month = {Feb}, Number = {2}, Pages = {97-107}, Title = {{Homeostatic plasticity in the developing nervous system.}}, Volume = {5}, Year = {2004}} @article{Ehlers2000, Annote = {Both acute and chronic changes in AMPA receptor (AMPAR) localization are critical for synaptic formation, maturation, and plasticity. Here I report that AMPARs are differentially sorted between recycling and degradative pathways following endocytosis. AMPAR sorting occurs in early endosomes and is regulated by synaptic activity and activation of AMPA and NMDA receptors. AMPAR intemalization triggered by NMDAR activation is Ca2+-dependent, requires protein phosphatases, and is followed by rapid membrane reinsertion. Furthermore, NMDAR-mediated AMPAR trafficking is regulated by PKA and accompanied by dephosphorylation and rephosphorylation of GluR1 subunits at a PKA site. In contrast, activation of AMPARs without NMDAR activation targets AMPARs to late endosomes and lysosomes, independent of Ca2+, protein phosphatases, or PKA. These results demonstrate that activity regulates AMPAR endocytic sorting, providing a potential mechanistic link between rapid and chronic changes in synaptic strength.}, Author = {M. D. Ehlers}, Journal = {Neuron}, Month = {Nov}, Number = {2}, Pages = {511-25}, Title = {{Reinsertion or degradation of AMPA receptors determined by activity-dependent endocytic sorting.}}, Volume = {28}, Year = {2000}} @article{Kennedy1983, Annote = {By three criteria, two biochemical and one immunochemical, the major postsynaptic density protein (mPSDp) is indistinguishable from the 50-kilodalton (kDa) alpha subunit of a brain calmodulin-dependent protein kinase. First, the two proteins comigrate on NaDodSO4/polyacrylamide gels. Second, iodinated tryptic peptide maps of the two are identical. Finally, a monoclonal antibody (6G9) that was raised against the protein kinase binds on immunoblots to a single 50 kDa band in crude brain homogenates and to both the alpha subunit of the purified kinase and the mPSDp from postsynaptic density fractions. The purified kinase holoenzyme also contains a 60-kDa subunit termed beta. A comparison of the peptide map of beta with the maps of 60-kDa proteins from the postsynaptic density fraction suggests that beta is present there but is not the only protein present in this molecular weight range. These results indicate that the calmodulin-dependent protein kinase is a major constituent of the postsynaptic density fraction and thus may be a component of type I postsynaptic densities.}, Author = {M. B. Kennedy and M. K. Bennett and N. E. Erondu}, Journal = {Proc Natl Acad Sci U S A}, Month = {Dec}, Number = {23}, Pages = {7357-61}, Title = {{Biochemical and immunochemical evidence that the "major postsynaptic density protein" is a subunit of a calmodulin-dependent protein kinase.}}, Volume = {80}, Year = {1983}} @article{Lendvai2000, Annote = {Do changes in neuronal structure underlie cortical plasticity? Here we used time-lapse two-photon microscopy of pyramidal neurons in layer 2/3 of developing rat barrel cortex to image the structural dynamics of dendritic spines and filopodia. We found that these protrusions were highly motile: spines and filopodia appeared, disappeared or changed shape over tens of minutes. To test whether sensory experience drives this motility we trimmed whiskers one to three days before imaging. Sensory deprivation markedly (approximately 40\%) reduced protrusive motility in deprived regions of the barrel cortex during a critical period around postnatal days (P)11-13, but had no effect in younger (P8-10) or older (P14-16) animals. Unexpectedly, whisker trimming did not change the density, length or shape of spines and filopodia. However, sensory deprivation during the critical period degraded the tuning of layer 2/3 receptive fields. Thus sensory experience drives structural plasticity in dendrites, which may underlie the reorganization of neural circuits.}, Author = {B. Lendvai and E. A. Stern and B. Chen and K. Svoboda}, Journal = {Nature}, Month = {Apr}, Number = {6780}, Pages = {876-81}, Title = {{Experience-dependent plasticity of dendritic spines in the developing rat barrel cortex in vivo.}}, Volume = {404}, Year = {2000}} @article{Contractor2002, Annote = {Ionotropic glutamate receptors mediate excitatory synaptic transmission at most central mammalian synapses. In addition to converting the chemical signal released from the presynaptic terminal to an electrical response in the postsynaptic neuron, these receptors are critically involved in activity-dependent, long-term changes in synaptic strength and, therefore, are central to processes thought to underlie learning and memory. Several mechanisms have been proposed to play roles in altering synaptic strength, and it is clear that there are several different forms of long-term synaptic plasticity in the mammalian brain. Here, we review recent evidence that some forms of synaptic strengthening rely on the modification of the glutamate receptor complement at synapses in response to activity-dependent processes.}, Author = {A. Contractor and S. F. Heinemann}, Journal = {Sci STKE}, Month = {Oct}, Number = {156}, Pages = {RE14}, Title = {{Glutamate receptor trafficking in synaptic plasticity.}}, Volume = {2002}, Year = {2002}} @article{Genoud2004, Annote = {Increased sensory stimulation in the adult whisker-to-barrel pathway induces the expression of BDNF as well as synapse formation in cortical layer IV. Here, we investigated whether BDNF plays a role in the alterations of connectivity between neurons by analyzing the ultrastructure of the BDNF heterozygote mouse, characterized by a reduced level of BDNF expression. Using serial section electron microscopy, we measured synapse density, spine morphology, and synaptic vesicle distribution to show that mice with a reduced level of BDNF have a barrel neuropil that is indistinguishable from wild-type controls. After 24 hr of whisker stimulation, however, there is no indication of synapse formation in the heterozygous mouse. Whereas the balance between excitatory and inhibitory synapses is modified in the controls, it remains constant in the heterozygotes. The distribution of synaptic vesicles in excitatory synapses is the same in heterozygous and wild-type mice and is not influenced by the stimulation paradigm. Spine volume, however, is unchanged by stimulation in the wild-type animals, but does increase significantly in the heterozygous animal. These results provide evidence that, in vivo, BDNF plays an important role in the structural rearrangement of adult cortical circuitry as a consequence of an increased sensory input.}, Author = {C. Genoud and G. W. Knott and K. Sakata and B. Lu and E. Welker}, Journal = {J Neurosci}, Month = {Mar}, Number = {10}, Pages = {2394-400}, Title = {{Altered synapse formation in the adult somatosensory cortex of brain-derived neurotrophic factor heterozygote mice.}}, Volume = {24}, Year = {2004}} @article{Knott2002, Annote = {During development, alterations in sensory experience modify the structure of cortical neurons, particularly at the level of the dendritic spine. Are similar adaptations involved in plasticity of the adult cortex? Here we show that a 24 hr period of single whisker stimulation in freely moving adult mice increases, by 36\%, the total synaptic density in the corresponding cortical barrel. This is due to an increase in both excitatory and inhibitory synapses found on spines. Four days after stimulation, the inhibitory inputs to the spines remain despite total synaptic density returning to pre-stimulation levels. Functional analysis of layer IV cells demonstrated altered response properties, immediately after stimulation, as well as four days later. These results indicate activity-dependent alterations in synaptic circuitry in adulthood, modifying the flow of sensory information into the cerebral cortex.}, Author = {G. W. Knott and C. Quairiaux and C. Genoud and E. Welker}, Journal = {Neuron}, Month = {Apr}, Number = {2}, Pages = {265-73}, Title = {{Formation of dendritic spines with GABAergic synapses induced by whisker stimulation in adult mice.}}, Volume = {34}, Year = {2002}} @article{McAllister1996, Annote = {Neurotrophins have been proposed to mediate several forms of activity-dependent competition in the central nervous system. A key element of such hypotheses is that neurotrophins act preferentially on active neurons; however, little direct evidence supports this postulate. We therefore examined, in ferret cortical brain slices, the interactions between activity and neurotrophins in regulating dendritic growth of layer 4 pyramidal neurons. Inhibition of spontaneous electrical activity, synaptic transmission, or L-type calcium channels each prevented the otherwise dramatic increase in dendritic arborizations elicited by brain-derived neurotrophic factor. In developing cortex, this requirement for conjoint neurotrophin signaling and activity provides a mechanism for selectively enhancing the growth and connectivity of active neurons.}, Author = {A. K. McAllister and L. C. Katz and D. C. Lo}, Journal = {Neuron}, Month = {Dec}, Number = {6}, Pages = {1057-64}, Title = {{Neurotrophin regulation of cortical dendritic growth requires activity.}}, Volume = {17}, Year = {1996}} @article{Zito2002, Annote = {Recent electron microscopic studies provide evidence that the adult cortex generates new synapses in response to sensory activity and that these structural changes can occur rapidly, within 24 hr of sensory stimulation. Together with progress imaging synapses in vivo, the stage appears set for advances in understanding the dynamics and mechanisms of experience-dependent synaptogenesis.}, Author = {K. Zito and K. Svoboda}, Journal = {Neuron}, Month = {Sep}, Number = {6}, Pages = {1015-1017}, Title = {{Activity-dependent synaptogenesis in the adult Mammalian cortex.}}, Volume = {35}, Year = {2002}} @article{Smart2000, Annote = {Dendritic spines undergo several types of transformations, ranging from growth to collapse, and from elongation to shortening, and they experience dynamic morphological activity on a rapid time scale. Changes in spine number and morphology occur under pathological conditions like excitotoxicity, but also during normal central nervous system development, during hormonal fluctuations, and in response to neural activity under physiological circumstances. We briefly review evidence for various types of alterations in spines, and discuss the possible molecular basis for changes in spine stability. Filamentous actin appears to be the most important cytoskeletal component of spines, and a growing list of actin-associated and actin-regulatory proteins has been reported to reside within spines. We conclude that spines contain two distinct pools of actin filaments (one stable, the other unstable) that provide the spine with both a stable core structure and a dynamic, complex shape. Finally, we review the current state of knowledge of actin filament regulation, based on studies in nonneuronal cells.}, Author = {F. M. Smart and S. Halpain}, Journal = {Hippocampus}, Number = {5}, Pages = {542-54}, Title = {{Regulation of dendritic spine stability.}}, Volume = {10}, Year = {2000}} @article{Halpain2003, Author = {S. Halpain}, Journal = {Nat Neurosci}, Month = {Feb}, Number = {2}, Pages = {101-102}, Title = {{Actin in a supporting role.}}, Volume = {6}, Year = {2003}} @article{Halpain2000, Annote = {Since early anatomical descriptions, the existence of dendritic spines has stimulated intense curiosity and speculation about their regulation and function. Research over the past three decades has described an impressive mutability in dendritic-spine number and morphology under a variety of physiological circumstances. Current evidence favors a proposed model in which two pools of actin filaments, one stable and the other dynamic, support both persistent spine structure and rapid spine motility. Potential functions of spine motility and dynamic actin include regulated protein scaffolding, retrograde signaling and synapse stabilization.}, Author = {S. Halpain}, Journal = {Trends Neurosci}, Month = {Apr}, Number = {4}, Pages = {141-146}, Title = {{Actin and the agile spine: how and why do dendritic spines dance?}}, Volume = {23}, Year = {2000}} @article{Sanes1999, Author = {J. R. Sanes and J. W. Lichtman}, Journal = {Nat Neurosci}, Month = {Jul}, Number = {7}, Pages = {597-604}, Title = {{Can molecules explain long-term potentiation?}}, Volume = {2}, Year = {1999}} @article{Schnell2002, Annote = {Excitatory synapses in the brain exhibit a remarkable degree of functional plasticity, which largely reflects changes in the number of synaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). However, mechanisms involved in recruiting AMPARs to synapses are unknown. Here we use hippocampal slice cultures and biolistic gene transfections to study the targeting of AMPARs to synapses. We show that AMPARs are localized to synapses through direct binding of the first two PDZ domains of synaptic PSD-95 (postsynaptic density protein of 95 kDa) to the AMPAR-associated protein, stargazin. Increasing the level of synaptic PSD-95 recruits new AMPARs to synapses without changing the number of surface AMPARs. At the same time, we show that stargazin overexpression drastically increases the number of extra-synaptic AMPARs, but fails to alter synaptic currents if synaptic PSD-95 levels are kept constant. Finally, we make compensatory mutations to both PSD-95 and stargazin to demonstrate the central role of direct interactions between them in determining the number of synaptic AMPARs.}, Author = {E. Schnell and M. Sizemore and S. Karimzadegan and L. Chen and D. S. Bredt and R. A. Nicoll}, Journal = {Proc Natl Acad Sci U S A}, Month = {Oct}, Number = {21}, Pages = {13902-13907}, Title = {{Direct interactions between PSD-95 and stargazin control synaptic AMPA receptor number.}}, Volume = {99}, Year = {2002}} @article{Grutzendler2002, Annote = {The structural dynamics of synapses probably has a crucial role in the development and plasticity of the nervous system. In the mammalian brain, the vast majority of excitatory axo-dendritic synapses occur on dendritic specializations called 'spines'. However, little is known about their long-term changes in the intact developing or adult animal. To address this question we developed a transcranial two-photon imaging technique to follow identified spines of layer-5 pyramidal neurons in the primary visual cortex of living transgenic mice expressing yellow fluorescent protein. Here we show that filopodia-like dendritic protrusions, extending and retracting over hours, are abundant in young animals but virtually absent from the adult. In young mice, within the 'critical period' for visual cortex development, approximately 73\% of spines remain stable over a one-month interval; most changes are associated with spine elimination. In contrast, in adult mice, the overwhelming majority of spines (approximately 96\%) remain stable over the same interval with a half-life greater than 13 months. These results indicate that spines, initially plastic during development, become remarkably stable in the adult, providing a potential structural basis for long-term information storage.}, Author = {J. Grutzendler and N. Kasthuri and W. B. Gan}, Journal = {Nature}, Month = {Dec}, Number = {6917}, Pages = {812-816}, Title = {{Long-term dendritic spine stability in the adult cortex.}}, Volume = {420}, Year = {2002}} @article{Penzes2001, Annote = {Spine function requires precise control of the actin cytoskeleton. Kalirin-7, a GDP/GTP exchange factor for Rac1, interacts with PDZ proteins such as PSD-95, colocalizing with PSD-95 at synapses of cultured hippocampal neurons. PSD-95 and Kalirin-7 interact in vivo and in heterologous expression systems. In primary cortical neurons, transfected Kalirin-7 is targeted to spines and increases the number and size of spine-like structures. A Kalirin-7 mutant unable to interact with PDZ proteins remains in the cell soma, inducing local formation of aberrant filopodial neurites. Kalirin-7 with an inactivated GEF domain reduces the number of spines below control levels. These results provide evidence that PDZ proteins target Kalirin-7 to the PSD, where it regulates dendritic morphogenesis through Rac1 signaling to the actin cytoskeleton.}, Author = {P. Penzes and R. C. Johnson and R. Sattler and X. Zhang and R. L. Huganir and V. Kambampati and R. E. Mains and B. A. Eipper}, Journal = {Neuron}, Month = {Jan}, Number = {1}, Pages = {229-42}, Title = {{The neuronal Rho-GEF Kalirin-7 interacts with PDZ domain-containing proteins and regulates dendritic morphogenesis.}}, Volume = {29}, Year = {2001}} @article{Okabe1999, Annote = {A postsynaptic density (PSD) protein, PSD-95, was tagged with green fluorescent protein (GFP-PSD-95) and expressed in cultured hippocampal neurons using recombinant adenoviruses. GFP-PSD-95 was selectively localized to excitatory postsynaptic sites. Time-lapse fluorescence imaging of hippocampal neurons revealed that >20\% of GFP-PSD-95 clusters turned over within 24 hours. The appearance rate of clusters was higher than the disappearance rate, and this difference accounted for the gradual increase of the cluster density observed in culture. Dynamics of PSD-95 clusters were also inhibited by blockers of excitatory synaptic transmission. Continual PSD turnover and its regulation by synaptic activity may be important in activity-dependent remodeling of neuronal connections.}, Author = {S. Okabe and H. D. Kim and A. Miwa and T. Kuriu and H. Okado}, Journal = {Nat Neurosci}, Month = {Sep}, Number = {9}, Pages = {804-11}, Title = {{Continual remodeling of postsynaptic density and its regulation by synaptic activity.}}, Volume = {2}, Year = {1999}} @article{Edwards1998, Author = {F. A. Edwards}, Journal = {Nature}, Month = {Jul}, Number = {6689}, Pages = {129-30}, Title = {{Dancing dendrites.}}, Volume = {394}, Year = {1998}} @article{Woolley1994, Annote = {In the adult female rat, the densities of dendritic spines and synapses on hippocampal CA1 pyramidal cells are dependent upon the ovarian steroid estradiol; moreover, spine and synapse density fluctuate naturally as ovarian steroid levels vary across the estrous cycle. To determine whether the effects of estradiol on dendritic spine density require activation of specific neurotransmitter systems, we have treated animals concurrently with estradiol and one of four selective neurotransmitter receptor antagonists: MK 801, a noncompetitive NMDA receptor antagonist; CGP 43487, a competitive NMDA receptor antagonist; NBQX, an AMPA receptor antagonist; or scopolamine, a muscarinic receptor antagonist. Our results indicate that the effects of estradiol can be blocked by treatment with either of the NMDA receptor antagonists, but treatment with an AMPA or muscarinic receptor antagonist has no effect on spine density. Thus, we have concluded that estradiol exerts its effect on hippocampal dendritic spine density via a mechanism requiring activation specifically of NMDA receptors.}, Author = {C. S. Woolley and B. S. McEwen}, Journal = {J Neurosci}, Month = {Dec}, Number = {12}, Pages = {7680-7687}, Title = {{Estradiol regulates hippocampal dendritic spine density via an N-methyl-D-aspartate receptor-dependent mechanism.}}, Volume = {14}, Year = {1994}} @article{Alonso2004, Annote = {Brain-derived neurotrophic factor (BDNF) is a potent modulator of synaptic transmission and plasticity in the CNS, acting both pre- and postsynaptically. We demonstrated recently that BDNF/TrkB signaling increases dendritic spine density in hippocampal CA1 pyramidal neurons. Here, we tested whether activation of the prominent ERK (MAPK) signaling pathway was responsible for BDNF's effects on spine growth. Slice cultures were transfected with enhanced yellow fluorescent protein (eYFP) by particle-mediated gene transfer, and CA1 pyramidal neurons were imaged by laser-scanning confocal microscopy. We confirmed that BDNF (24 h) increases spine density in apical dendrites of CA1 neurons. The MEK (ERK kinase) inhibitors PD98059 and U0126 completely prevented the increase in spine density induced by BDNF, without having an effect on spine density by themselves. In contrast to its actions on cortical pyramidal neurons, BDNF had minor and rather localized effects on dendritic complexity in hippocampal pyramidal neurons, increasing the total length, but not the branching of apical dendrites within CA1 stratum radiatum, without affecting basal dendrites in stratum oriens. Our results support the hypothesis that the ERK-signaling pathway not only mediates long-term synaptic plasticity and hippocampal-dependent learning, but it is also involved in the structural remodeling of excitatory spine synapses triggered by neurotrophins.}, Author = {M. Alonso and J. H. Medina and L. Pozzo-Miller}, Journal = {Learn Mem}, Month = {Mar}, Number = {2}, Pages = {172-178}, Title = {{ERK1/2 activation is necessary for BDNF to increase dendritic spine density in hippocampal CA1 pyramidal neurons.}}, Volume = {11}, Year = {2004}} @article{Cotman1974, Author = {C. W. Cotman and G. Banker and L. Churchill and D. Taylor}, Journal = {J Cell Biol}, Month = {Nov}, Number = {2 Pt 1}, Pages = {441-55}, Title = {{Isolation of postsynaptic densities from rat brain.}}, Volume = {63}, Year = {1974}} @article{Banker1974, Author = {G. Banker and L. Churchill and C. W. Cotman}, Journal = {J Cell Biol}, Month = {Nov}, Number = {2 Pt 1}, Pages = {456-65}, Title = {{Proteins of the postsynaptic density.}}, Volume = {63}, Year = {1974}} @article{Cohen1977, Author = {R. S. Cohen and F. Blomberg and K. Berzins and P. Siekevitz}, Journal = {J Cell Biol}, Month = {Jul}, Number = {1}, Pages = {181-203}, Title = {{The structure of postsynaptic densities isolated from dog cerebral cortex. I. Overall morphology and protein composition.}}, Volume = {74}, Year = {1977}} @article{Gray1959, Author = {E.G. Gray}, Journal = {Nature}, Number = {183}, Pages = {1592-1594}, Title = {{Electron microscopy of synaptic contacts on dendritic spines of the cerebral cortex}}, Year = {1959}} @article{Blomberg1977, Author = {F. Blomberg and R. S. Cohen and P. Siekevitz}, Journal = {J Cell Biol}, Month = {Jul}, Number = {1}, Pages = {204-25}, Title = {{The structure of postsynaptic densities isolated from dog cerebral cortex. II. Characterization and arrangement of some of the major proteins within the structure.}}, Volume = {74}, Year = {1977}} @article{Yuste2001, Annote = {Dendritic spines are morphological specializations that receive synaptic inputs and compartmentalize calcium. In spite of a long history of research, the specific function of spines is still not well understood. Here we review the current status of the relation between morphological changes in spines and synaptic plasticity. Since Cajal and Tanzi proposed that changes in the structure of the brain might occur as a consequence of experience, the search for the morphological correlates of learning has constituted one of the central questions in neuroscience. Although there are scores of studies that encompass this wide field in many species, in this review we focus on experimental work that has analyzed the morphological consequences of hippocampal long-term potentiation (LTP) in rodents. Over the past two decades many studies have demonstrated changes in the morphology of spines after LTP, such as enlargements of the spine head and shortenings of the spine neck. Biophysically, these changes translate into an increase in the synaptic current injected at the spine, as well as shortening of the time constant for calcium compartmentalization. In addition, recent online studies using time-lapse imaging have reported increased spinogenesis. The currently available data show a strong correlation between synaptic plasticity and morphological changes in spines, although at the same time, there is no evidence that these morphological changes are necessary or sufficient for the induction or maintenance of LTP. Still, they highlight once more how form and function go hand in hand in the central nervous system.}, Author = {R. Yuste and T. Bonhoeffer}, Journal = {Annu Rev Neurosci}, Pages = {1071-89}, Title = {{Morphological changes in dendritic spines associated with long-term synaptic plasticity.}}, Volume = {24}, Year = {2001}} @article{Trachtenberg2002, Annote = {Do new synapses form in the adult cortex to support experience-dependent plasticity? To address this question, we repeatedly imaged individual pyramidal neurons in the mouse barrel cortex over periods of weeks. We found that, although dendritic structure is stable, some spines appear and disappear. Spine lifetimes vary greatly: stable spines, about 50\% of the population, persist for at least a month, whereas the remainder are present for a few days or less. Serial-section electron microscopy of imaged dendritic segments revealed retrospectively that spine sprouting and retraction are associated with synapse formation and elimination. Experience-dependent plasticity of cortical receptive fields was accompanied by increased synapse turnover. Our measurements suggest that sensory experience drives the formation and elimination of synapses and that these changes might underlie adaptive remodelling of neural circuits.}, Author = {J. T. Trachtenberg and B. E. Chen and G. W. Knott and G. Feng and J. R. Sanes and E. Welker and K. Svoboda}, Journal = {Nature}, Month = {Dec}, Number = {6917}, Pages = {788-94}, Title = {{Long-term in vivo imaging of experience-dependent synaptic plasticity in adult cortex.}}, Volume = {420}, Year = {2002}} @article{Cline2001, Annote = {In vivo studies indicate that synaptic activity promotes dendritic arbor elaboration at early stages of brain development. At later stages of development, synaptic activity stabilizes dendritic structure. The different roles of synaptic activity with respect to structural plasticity probably reflect the regulated spatiotemporal expression of key components within signaling pathways.}, Author = {H. T. Cline}, Journal = {Curr Opin Neurobiol}, Month = {Feb}, Number = {1}, Pages = {118-26}, Title = {{Dendritic arbor development and synaptogenesis.}}, Volume = {11}, Year = {2001}} @article{Peters1970, Author = {A. Peters and I.R. Kaiserman-Abramof}, Journal = {Am. J. Anat.}, Number = {127}, Pages = {321-355}, Title = {{The small pyramidal neuron of the rat cerebral cortex. The perikaryon, dendrites and spines}}, Year = {1970}} @article{Jontes2000, Author = {J. D. Jontes and S. J. Smith}, Journal = {Neuron}, Month = {Jul}, Number = {1}, Pages = {11-14}, Title = {{Filopodia, spines, and the generation of synaptic diversity.}}, Volume = {27}, Year = {2000}} @article{Dailey1996, Annote = {Time-lapse fluorescence confocal microscopy was used to directly visualize the formation and dynamics of postsynaptic target structures (i.e., dendritic branches and spines) on pyramidal neurons within developing tissue slices. Within a 2 week period of time, pyramidal neurons in cultured slices derived from early postnatal rat (postnatal days 2-7) developed complex dendritic arbors bearing numerous postsynaptic spines. At early stages (1-2 d in vitro), many fine filopodial protrusions on dendrite shafts rapidly extended (maximum rate approximately 2.5 microM/minute) and retracted (median filopodial lifetime, 10 min), but some filopodia transformed into growth cones and nascent dendrite branches. As dendritic arbors matured, the population of fleeting lateral filopodia was replaced by spine-like structures having a low rate of turnover. This developmental progression involved a transitional stage in which dendrites were dominated by persistent (up to 22 hr) but dynamic spiny protrusions (i.e., protospines) that showed substantial changes in length and shape on a timescale of minutes. These observations reveal a highly dynamic state of postsynaptic target structures that may actively contribute to the formation and plasticity of synaptic connections during CNS development.}, Author = {M. E. Dailey and S. J. Smith}, Journal = {J Neurosci}, Month = {May}, Number = {9}, Pages = {2983-94}, Title = {{The dynamics of dendritic structure in developing hippocampal slices.}}, Volume = {16}, Year = {1996}} @article{Marrs2001, Annote = {The dynamics of postsynaptic density (PSD) formation and remodeling were investigated in live developing hippocampal tissue slices. Time lapse imaging of transfected neurons expressing GFP-tagged PSD95, a prominent PSD protein, revealed that up to 40\% of PSDs in developing dendrites are structurally dynamic; they rapidly (<15 min) appear or disappear, but also grow, shrink and move within shafts and spines. New spines containing PSDs were formed by conversion of dynamic filopodia-like spine precursors in which PSDs appeared de novo, or by direct extension of spines or spine precursors carrying preformed PSDs from the shaft. PSDs are therefore highly dynamic structures that can undergo rapid structural alteration within dendrite shafts, spines and spine precursors, permitting rapid formation and remodeling of synaptic connections in developing CNS tissues.}, Author = {G. S. Marrs and S. H. Green and M. E. Dailey}, Journal = {Nat Neurosci}, Month = {Oct}, Number = {10}, Pages = {1006-13}, Title = {{Rapid formation and remodeling of postsynaptic densities in developing dendrites.}}, Volume = {4}, Year = {2001}} @article{Okabe2001, Annote = {Hippocampal pyramidal neurons in culture showed a developmental shift in synapse distribution from dendritic shafts to spines. Using dual wavelength time-lapse fluorescence microscopy, we analyzed the morphogenesis of three synaptic components: dendritic spines, postsynaptic densities (PSDs), and presynaptic vesicles. Local assembly of a major PSD protein, PSD-95, was spatially and temporally correlated with spine morphogenesis. Clustering of postsynaptic PSD-95 and that of a predominant synaptic vesicle protein, synaptophysin, were also correlated. In contrast, pre-existing PSD-95 clusters in dendritic shafts were preferentially eliminated without promoting spine formation. The local and stepwise assembly of synaptic components at the contact sites between dendritic protrusions and axons explains the developmental remodeling of excitatory synapses.}, Author = {S. Okabe and A. Miwa and H. Okado}, Journal = {J Neurosci}, Month = {Aug}, Number = {16}, Pages = {6105-14}, Title = {{Spine formation and correlated assembly of presynaptic and postsynaptic molecules.}}, Volume = {21}, Year = {2001}} @article{Scott2001, Annote = {Recent technical advances have made possible the visualization and genetic manipulation of individual dendritic trees. These studies have led to the identification and characterization of molecules that are important for different aspects of dendritic development. Although much remains to be learned, the existing knowledge has allowed us to take initial steps toward a comprehensive understanding of how complex dendritic trees are built. In this review, we describe recent advances in our understanding of the molecular mechanisms underlying dendritic morphogenesis, and discuss their cell-biological implications.}, Author = {E. K. Scott and L. Luo}, Journal = {Nat Neurosci}, Month = {Apr}, Number = {4}, Pages = {359-65}, Title = {{How do dendrites take their shape?}}, Volume = {4}, Year = {2001}} @article{Nakayama2000b, Annote = {Rac is a member of the Rho family of small GTPases and acts as a molecular switch. When GTP-bound, Rac binds specific effectors to induce downstream signaling events, including actin cytoskeletal rearrangements (Hall, Science 1998;279:509-514). Herein we review the recent evidence suggesting that Rac is involved in the morphogenesis of dendritic spines (Luo et al., Nature 1996;379:837-840; Nakayama et al., J Neurosci 2000; 20:5329-5338). In addition, we discuss how Rac activity is regulated by guanine nucleotide exchange factors, which may be further regulated by extracellular factors. Thus, the Rac signal transduction pathway may provide links between extracellular ligands or synaptic activity and the regulation of the actin cytoskeleton in spine morphogenesis.}, Author = {A. Y. Nakayama and L. Luo}, Journal = {Hippocampus}, Number = {5}, Pages = {582-586}, Title = {{Intracellular signaling pathways that regulate dendritic spine morphogenesis.}}, Volume = {10}, Year = {2000}} @article{McAllister2000, Annote = {Proper growth and branching of dendrites are crucial for nervous system function; patterns of dendritic arborization determine the nature and amount of innervation that a neuron receives and specific dendritic membrane properties define its computational capabilities. Until recently, there was relatively little known about the cellular and molecular mechanisms of dendritic growth, perhaps because dendrites were historically considered to be intrinsically determined, passive elements in the formation of connections in the nervous system. In the last few years, however, overwhelming evidence has accumulated indicating that dendritic growth is remarkably dynamic and responsive to environmental signals, including guidance molecules and levels and patterns of activity. This manuscript reviews our current understanding of the cellular and molecular mechanisms of dendritic growth, the influence of activity in sculpting specific patterns of dendritic arbors, and a potential integral role for dendrites in activity-dependent development of circuits in the nervous system.}, Author = {A. K. McAllister}, Journal = {Cereb Cortex}, Month = {Oct}, Number = {10}, Pages = {963-73}, Title = {{Cellular and molecular mechanisms of dendrite growth.}}, Volume = {10}, Year = {2000}} @article{Jan2003, Annote = {Dendrite development is an important and unsolved problem in neuroscience. The nervous system is composed of a vast number of neurons with strikingly different morphology. Neurons are highly polarized cells with distinct subcellular compartments, including one or multiple dendritic processes arising from the cell body, and a single, extended axon. Communications between neurons involve synapses formed between axons of the presynaptic neurons and dendrites of the postsynaptic neurons. Extensive studies over the past decade have identified many molecules underlying axonal outgrowth and pathfinding. In contrast, the control of dendrite development is still much less well understood. However, recent progress has begun to shed light on the molecular mechanisms that orchestrate dendrite growth, arborization, and guidance.}, Author = {Y. N. Jan and L. Y. Jan}, Journal = {Neuron}, Month = {Oct}, Number = {2}, Pages = {229-42}, Title = {{The control of dendrite development.}}, Volume = {40}, Year = {2003}} @article{Ackermann2003, Annote = {Morphological changes in dendritic spines have been implicated in connective plasticity in brain circuitry, but the underlying pathway leading from synaptic transmission to structural change is unknown. Using primary neurons expressing GFP-tagged proteins, we found that profilin, a regulator of actin polymerization, is targeted to spine heads when postsynaptic NMDA receptors are activated and that actin-based changes in spine shape are concomitantly blocked. Profilin targeting was triggered by electrical stimulation patterns known to induce the long-term changes in synaptic responsiveness associated with memory formation. These results suggest that, in addition to electrophysiological changes, NMDA receptor activation initiates changes in the actin cytoskeleton of dendritic spines that stabilize synaptic structure.}, Author = {M. Ackermann and A. Matus}, Journal = {Nat Neurosci}, Keywords = {Matus}, Month = {Nov}, Number = {11}, Pages = {1194-200}, Title = {{Activity-induced targeting of profilin and stabilization of dendritic spine morphology.}}, Volume = {6}, Year = {2003}} @article{Luo2002, Annote = {The actin cytoskeleton plays a major role in morphological development of neurons and in structural changes of adult neurons. This article reviews the myriad functions of actin and myosin in axon initiation, growth, guidance and branching, in morphogenesis of dendrites and dendritic spines, in synapse formation and stability, and in axon and dendrite retraction. Evidence is presented that signaling pathways involving the Rho family of small GTPases are key regulators of actin polymerization and myosin function in the context of different aspects of neuronal morphogenesis. These studies support an emerging theme: Different aspects of neuronal morphogenesis may involve regulation of common core signaling pathways, in particular the Rho GTPases.}, Author = {L. Luo}, Journal = {Annu Rev Cell Dev Biol}, Pages = {601-35}, Title = {{Actin cytoskeleton regulation in neuronal morphogenesis and structural plasticity.}}, Volume = {18}, Year = {2002}} @article{Ahmadian1997, Annote = {RasGAPs supply a catalytic residue, termed the arginine finger,into the active site of Ras thereby stabilizing the transition state of the GTPase reaction and increasing the reaction rate by more than one thousand-fold, in good agreement with the structure of the Ras.RasGAP complex.}, Author = {M. R. Ahmadian and P. Stege and K. Scheffzek and A. Wittinghofer}, Journal = {Nat Struct Biol}, Month = {Sep}, Number = {9}, Pages = {686-689}, Title = {{Confirmation of the arginine-finger hypothesis for the GAP-stimulated GTP-hydrolysis reaction of Ras.}}, Volume = {4}, Year = {1997}} @article{Alpar2003, Annote = {The small G protein p21Ras is a critical molecular switch for relaying neurotrophic actions and is essential for normal functioning and plasticity of the nervous system. In this study, the morphogenetic effects of p21Ras were investigated on neurons in vivo. Morphological changes of layers II/III and Vb commissural pyramidal neurons of the primary somatosensory cortex were analyzed in transgenic mice expressing permanently active p21H-RasVal12 in postmitotic neurons. Pyramidal cells were retrogradely labelled with biotinylated dextran amine and subsequently traced using Neurolucida. Compared with wild-type mice, transgenic animals showed a significant increase in the surface area and volume of basal dendrites on the proximal and intermediate segments in layers II/III and on further distal segments in layer V. In addition, the surface area and volume of the trunk and of the proximal segments of oblique branches of apical dendrites were enlarged in both layers. Sholl analyses of basal and apical dendrites showed a significant increase in dendritic complexity of layer V neurons. A positive correlation was observed between the size of the basal dendrite and the neuronal soma size in the transgenic population, indicating that growth-promoting effects of p21H-RasVal12 affect both cellular compartments in parallel. However, the dendritic surface correlated with the number of tips and dendritic stem diameter in both wild-type and transgenic populations, demonstrating that these relations represent rather conservative design principles in dendritic morphology. The data presented here suggest an important role of p21Ras-dependent signaling in the final differentiation and maintenance of dendritic morphology.}, Author = {A. Alpar and K. Palm and A. Schierwagen and T. Arendt and U. Gartner}, Journal = {J Comp Neurol}, Month = {Dec}, Number = {1}, Pages = {119-33}, Title = {{Expression of constitutively active p21H-rasval12 in postmitotic pyramidal neurons results in increased dendritic size and complexity.}}, Volume = {467}, Year = {2003}} @article{Alpar2004, Annote = {Morphological features of interneuronal adaptation to an altered, more complex neuronal architecture have been investigated in p21H-Ras(Val12) transgenic mice. This transgenic strain serves as a model for studying the morphogenetic role of the G-protein p21Ras on cortical principal neurons. We have recently demonstrated that postmitotic expression of constitutively active p21H-Ras(Val12) in the neocortical pyramidal cell population results in increased size and dendritic complexity of the affected neurons, leading to an enlarged cortical volume. Interneurons do not express the transgene and are therefore excluded from direct, intrinsic p21H-Ras(Val12) effects. In the present study, immunolabelling of gamma-amino-butyric-acid (GABA), and of the calcium-binding proteins parvalbumin, calbindin and calretinin revealed that in the transgenic mice local circuit neurons are not increased in either somal size or number and their main morphological characteristics are preserved. However, the dendritic arbour of interneurons was found to be extended, at least in the vertical dimension, to follow the cortical expansion. Immunostaining for the vesicular GABA transporter revealed a denser inhibitory innervation of p21H-Ras(Val12)-expressing pyramidal cell perikarya than in those of wild-type animals, while the overall density of inhibitory axon terminals within the cortex was decreased in the transgenic animals as a consequence of cortical expansion. The findings of the present study demonstrate the morphogenetic capacity of interneurons for adapting to morphological alterations of principal neurons in the cerebral cortex.}, Author = {A. Alpar and G. Seeger and W. Hartig and T. Arendt and U. Gartner}, Journal = {Brain Res Bull}, Month = {Jan}, Number = {4}, Pages = {335-43}, Title = {{Adaptive morphological changes of neocortical interneurons in response to enlarged and more complex pyramidal cells in p21H-Ras(Val12) transgenic mice.}}, Volume = {62}, Year = {2004}} @article{Bading1991, Annote = {The N-methyl-D-aspartate (NMDA) receptor, a subtype of glutamate receptors, plays a key role in synaptic plasticity in the nervous system. After NMDA receptor activation, calcium entry into the postsynaptic neuron is a critical initial event. However, the subsequent mechanisms by which the NMDA receptor signal is processed are incompletely understood. Stimulation of cultured rat hippocampal cells with glutamate resulted in the rapid and transient tyrosine phosphorylation of a 39-kilodalton protein (p39). Tyrosine phosphorylation of p39 was triggered by the NMDA receptor and required an influx of Ca2+ from the extracellular medium. Because p39 was found to be highly related or identical to the microtubule-associated protein 2 kinase, the NMDA receptor signal may be processed by a sequential activation of protein kinases.}, Author = {H. Bading and M. E. Greenberg}, Journal = {Science}, Month = {Aug}, Number = {5022}, Pages = {912-914}, Title = {{Stimulation of protein tyrosine phosphorylation by NMDA receptor activation.}}, Volume = {253}, Year = {1991}} @article{Bailey1993, Author = {C. H. Bailey and E. R. Kandel}, Journal = {Annu Rev Physiol}, Pages = {397-426}, Title = {{Structural changes accompanying memory storage.}}, Volume = {55}, Year = {1993}} @article{Barria2002, Annote = {To elucidate mechanisms controlling the number and subunit composition of synaptic NMDA-Rs in hippocampal slice neurons, the NR1, NR2A, and NR2B subunits were optically and electrophysiologically tagged. The NR2 subunit directs delivery of receptors to synapses with different rules controlling NR2A and NR2B. Synaptic incorporation of NR2B-containing receptors is not limited by synaptic transmission nor enhanced by increased subunit expression. NR2A-containing receptors whose expression normally increases with age replace synaptic NR2B-containing receptors. Replacement is enhanced by increased NR2A expression and requires synaptic activity. Surprisingly, spontaneously released transmitter acting on synaptic NMDA-Rs is sufficient for replacement and reduces NMDA-R responses. Thus, as with AMPA-Rs, synaptic trafficking of NMDA-Rs is tightly regulated and has subunit-specific rules with functionally important consequences.}, Author = {A. Barria and R. Malinow}, Journal = {Neuron}, Month = {Jul}, Number = {2}, Pages = {345-53}, Title = {{Subunit-specific NMDA receptor trafficking to synapses.}}, Volume = {35}, Year = {2002}} @article{Bennett1983, Annote = {A calcium and calmodulin-dependent protein kinase has been purified from rat brain. It was monitored during the purification by its ability to phosphorylate the synaptic vesicle-associated protein, synapsin I. A 300-fold purification was sufficient to produce kinase that is 90-95\% pure as determined by scans of stained sodium dodecyl sulfate-polyacrylamide gels and has a specific activity of 2.9 mumol of 32P transferred per min/mg of protein. Thus, the kinase is a relatively abundant brain enzyme, perhaps comprising as much as 0.3\% of the total brain protein. The Stokes radius (95 A) and sedimentation coefficient (16.4 S) of the kinase indicate a holoenzyme molecular weight of approximately 650,000. The holoenzyme is composed of three subunits as judged by their co-migration with kinase activity during the purification steps and co-precipitation with kinase activity by a specific anti-kinase monoclonal antibody. The three subunits have molecular weights of 50,000, 58,000, and 60,000, and have been termed alpha, beta', and beta, respectively. The alpha- and beta-subunits are distinct peptides, however, beta' may have been generated from beta by proteolysis. All three of these subunits bind calmodulin in the presence of calcium and are autophosphorylated under conditions in which the kinase is active. The subunits are present in a ratio of about 3 alpha-subunits to 1 beta/beta'-subunit. We therefore postulate that the 650,000-Da holoenzyme consists of approximately 9 alpha-subunits and 3 beta/beta'-subunits. The abundance of this calmodulin-dependent protein kinase indicates that its activation is likely to be an important biochemical response to increases in calcium ion concentration in neuronal tissue.}, Author = {M. K. Bennett and N. E. Erondu and M. B. Kennedy}, Journal = {J Biol Chem}, Month = {Oct}, Number = {20}, Pages = {12735-44}, Title = {{Purification and characterization of a calmodulin-dependent protein kinase that is highly concentrated in brain.}}, Volume = {258}, Year = {1983}} @article{Bonhoeffer2002, Annote = {Throughout the history of neuroscience, dendritic spines have been considered stable structures, but in recent years, imaging techniques have revealed that spines are constantly changing shape. Spine motility is difficult to categorize, has different forms, and possibly even represents multiple phenomena. It is influenced by synaptic transmission, intracellular calcium, and a multitude of ions and other molecules. An actin-based cascade mediates this phenomenon, and while the precise signaling pathways are still unclear, the Rho family of GTPases could well be a "common denominator" controlling spine morphology. One role of spine motility might be to enable a searching function during synaptogenesis, allowing for more efficacious neuronal connectivity in the neuronal thicket. This idea revisits concepts originally formulated by Cajal, who proposed over a hundred years ago that spines might help to increase and modify synaptic connections.}, Author = {T. Bonhoeffer and R. Yuste}, Journal = {Neuron}, Month = {Sep}, Number = {6}, Pages = {1019-27}, Title = {{Spine motility. Phenomenology, mechanisms, and function.}}, Volume = {35}, Year = {2002}} @article{Brewer1993, Annote = {We have systematically optimized the concentrations of 20 components of a previously published serum-free medium (Brewer and Cotman, Brain Res 494: 65-74, 1989) for survival of rat embryonic hippocampal neurons after 4 days in culture. This serum-free medium supplement, B27, produced neuron survival above 60\%, independent of plating density above 160 plated cells/mm2. For isolated cells (< 100 cells/mm2), survival at 4 days was still above 45\%, but could be rescued to the 60\% level at 40 cells/mm2 by simply applying a coverslip on top of the cells. This suggests a need for additional trophic factors. High survival was achieved with osmolarity lower than found in Dulbecco's Modified Eagle's Medium (DMEM), and by reducing cysteine and glutamine concentrations and by the elimination of toxic ferrous sulphate found in DME/F12. Neurobasal is a new medium that incorporates these modifications to DMEM. In B27/Neurobasal, glial growth is reduced to less than 0.5\% of the nearly pure neuronal population, as judged by immunocytochemistry for glial fibrillary acidic protein and neuron-specific enolase. Excellent long-term viability is achieved after 4 weeks in culture with greater than 90\% viability for cells plated at 640/mm2 and greater than 50\% viability for cells plated at 160/mm2. Since the medium also supports the growth of neurons from embryonic rat striatum, substantia nigra, septum, and cortex, and neonatal dentate gyrus and cerebellum (Brewer, in preparation), support for other neuron types is likely. B27/Neurobasal should be useful for in vitro studies of neuronal toxicology, pharmacology, electrophysiology, gene expression, development, and effects of growth factors and hormones.}, Author = {G. J. Brewer and J. R. Torricelli and E. K. Evege and P. J. Price}, Journal = {J Neurosci Res}, Month = {Aug}, Number = {5}, Pages = {567-76}, Title = {{Optimized survival of hippocampal neurons in B27-supplemented Neurobasal, a new serum-free medium combination.}}, Volume = {35}, Year = {1993}} @article{Chen1998, Annote = {Ca2+ influx through N-methyl-D-aspartate- (NMDA-) type glutamate receptors plays a critical role in synaptic plasticity in the brain. One of the proteins activated by the increase in Ca2+ is CaM kinase II (CaMKII). Here, we report a novel synaptic Ras-GTPase activating protein (p135 SynGAP) that is a major component of the postsynaptic density, a complex of proteins associated with synaptic NMDA receptors. p135 SynGAP is almost exclusively localized at synapses in hippocampal neurons where it binds to and closely colocalizes with the scaffold protein PSD-95 and colocalizes with NMDA receptors. The Ras-GTPase activating activity of p135 SynGAP is inhibited by phosphorylation by CaMKII located in the PSD protein complex. Inhibition of p135 SynGAP by CaMKII will stop inactivation of GTP-bound Ras and thus could result in activation of the mitogen-activated protein (MAP) kinase pathway in hippocampal neurons upon activation of NMDA receptors.}, Author = {H. J. Chen and M. Rojas-Soto and A. Oguni and M. B. Kennedy}, Journal = {Neuron}, Month = {May}, Number = {5}, Pages = {895-904}, Title = {{A synaptic Ras-GTPase activating protein (p135 SynGAP) inhibited by CaM kinase II.}}, Volume = {20}, Year = {1998}} @article{Cho1992, Annote = {In CNS synapses, the synaptic junctional complex with associated postsynaptic density is presumed to contain proteins responsible for adhesion between pre- and postsynaptic membranes and for postsynaptic signal transduction. We have found that a prominent, brain-specific protein (PSD-95) enriched in the postsynaptic density fraction from rat brain is highly similar to the Drosophila lethal(1)discs-large-1 (dlg) tumor suppressor protein. The dlg protein is associated with septate junctions in developing flies and contains a guanylate kinase domain that is required for normal control of cell division. The sequence similarity between dlg and PSD-95 suggests that molecular mechanisms critical for growth control in developing organisms may also regulate synapse formation, stabilization, or function in the adult brain.}, Author = {K. O. Cho and C. A. Hunt and M. B. Kennedy}, Journal = {Neuron}, Keywords = {psd95}, Month = {Nov}, Number = {5}, Pages = {929-42}, Title = {{The rat brain postsynaptic density fraction contains a homolog of the Drosophila discs-large tumor suppressor protein.}}, Volume = {9}, Year = {1992}} @article{Constantine-Paton1990, Author = {M. Constantine-Paton and H. T. Cline and E. Debski}, Journal = {Annu Rev Neurosci}, Pages = {129-54}, Title = {{Patterned activity, synaptic convergence, and the NMDA receptor in developing visual pathways.}}, Volume = {13}, Year = {1990}} @article{Craven1999, Annote = {During synaptic development, proteins aggregate at specialized pre- and postsynaptic structures. Mechanisms that mediate protein clustering at these sites remain unknown. To investigate this process, we analyzed synaptic targeting of a postsynaptic density protein, PSD-95, by expressing green fluorescent protein- (GFP-) tagged PSD-95 in cultured hippocampal neurons. We find that postsynaptic clustering relies on three elements of PSD-95: N-terminal palmitoylation, the first two PDZ domains, and a C-terminal targeting motif. In contrast, disruptions of PDZ3, SH3, or guanylate kinase (GK) domains do not affect synaptic targeting. Palmitoylation is sufficient to target the diffusely expressed SAP-97 to synapses, and palmitoylation cannot be replaced with alternative membrane association motifs, suggesting that a specialized synaptic lipid environment mediates postsynaptic clustering. The requirements for PDZ domains and a C-terminal domain of PSD-95 indicate that protein-protein interactions cooperate with lipid interactions in synaptic targeting.}, Author = {S. E. Craven and A. E. El-Husseini and D. S. Bredt}, Journal = {Neuron}, Month = {Mar}, Number = {3}, Pages = {497-509}, Title = {{Synaptic targeting of the postsynaptic density protein PSD-95 mediated by lipid and protein motifs.}}, Volume = {22}, Year = {1999}} @article{DiNitto2003, Annote = {Modular domains that recognize and target intracellular membranes play a critical role in the assembly, localization, and function of signaling and trafficking complexes in eukaryotic cells. Large domain families, including PH, FYVE, PX, PHD, and C2 domains, combine specific, nonspecific, and multivalent interactions to achieve selective membrane targeting. Despite structural and functional diversity, general features of lipid recognition are evident in the various membrane-targeting mechanisms.}, Author = {J. P. DiNitto and T. C. Cronin and D. G. Lambright}, Journal = {Sci STKE}, Month = {Dec}, Number = {213}, Pages = {re16}, Title = {{Membrane recognition and targeting by lipid-binding domains.}}, Volume = {2003}, Year = {2003}} @article{Drugan2000, Annote = {Pleckstrin homology domains are structurally conserved functional domains that can undergo both protein/protein and protein/lipid interactions. Pleckstrin homology domains can mediate inter- and intra-molecular binding events to regulate enzyme activity. They occur in numerous proteins including many that interact with Ras superfamily members, such as p120 GAP. The pleckstrin homology domain of p120 GAP is located in the NH(2)-terminal, noncatalytic region of p120 GAP. Overexpression of the noncatalytic domains of p120 GAP may modulate Ras signal transduction pathways. Here, we demonstrate that expression of the isolated pleckstrin homology domain of p120 GAP specifically inhibits Ras-mediated signaling and transformation but not normal cellular growth. Furthermore, we show that the pleckstrin homology domain binds the catalytic domain of p120 GAP and interferes with the Ras/GAP interaction. Thus, we suggest that the pleckstrin homology domain of p120 GAP may specifically regulate the interaction of Ras with p120 GAP via competitive intra-molecular binding.}, Author = {J. K. Drugan and K. Rogers-Graham and T. Gilmer and S. Campbell and G. J. Clark}, Journal = {J Biol Chem}, Month = {Nov}, Number = {45}, Pages = {35021-35027}, Title = {{The Ras/p120 GTPase-activating protein (GAP) interaction is regulated by the p120 GAP pleckstrin homology domain.}}, Volume = {275}, Year = {2000}} @article{Dudek2001, Annote = {Mitogen-activated protein kinase (MAPK) has been identified as a potential element in regulating excitability, long-term potentiation (LTP), and gene expression in hippocampal neurons. The objective of the present study was to determine whether the pattern and intensity of synaptic activity could differentially regulate MAPK phosphorylation via selective activation of different modes of calcium influx into CA1 pyramidal neurons. An antibody specific for the phosphorylated (active) form of MAPK was used to stain sections from hippocampal slices, which were first stimulated in vitro. LTP-inducing stimulation [theta-burst (TBS) and 100 Hz] was effective in inducing intense staining in both dendritic and somatic compartments of CA1 neurons. Phosphorylation of MAPK was also induced, however, with stimulation frequencies (3-10 Hz) not typically effective in inducing LTP. Intensity and extent of staining was better correlated with the spread of population spikes across the CA1 subfield than with frequency (above 3 Hz). Experiments using inhibitors of NMDA receptors and voltage-sensitive calcium channels (VSCCs) revealed that, although MAPK is activated after both TBS and 5 Hz stimulation, the relative contribution of calcium through L-type calcium channels differs. Blockade of NMDA receptors alone was sufficient to prevent MAPK phosphorylation in response to 5 Hz stimulation, whereas inhibitors of both NMDA receptors and VSCCs were necessary for inhibition of the TBS-induced staining. We conclude that the intensity and frequency of synaptic input to CA1 hippocampal neurons are critically involved in determining the path by which second-messenger cascades are activated to activate MAPK.}, Author = {S. M. Dudek and R. D. Fields}, Journal = {J Neurosci}, Month = {Jan}, Number = {2}, Pages = {RC122}, Title = {{Mitogen-activated protein kinase/extracellular signal-regulated kinase activation in somatodendritic compartments: roles of action potentials, frequency, and mode of calcium entry.}}, Volume = {21}, Year = {2001}} @article{Ehlers2003, Annote = {Experience-dependent remodeling of the postsynaptic density (PSD) is critical for synapse formation and plasticity in the mammalian brain. Here, in cultured rat hippocampal neurons, I found long-lasting, global changes in the molecular composition of the PSD dictated by synaptic activity. These changes were bidirectional, reversible, modular, and involved multiple classes of PSD proteins. Moreover, activity-dependent remodeling was accompanied by altered protein turnover, occurred with corresponding increases or decreases in ubiquitin conjugation of synaptic proteins and required proteasome-mediated degradation. These modifications, in turn, reciprocally altered synaptic signaling to the downstream effectors CREB (cyclic AMP response element binding protein) and ERK-MAPK (extracellular signal regulated kinase-MAP kinase). These results indicate that activity regulates postsynaptic composition and signaling through the ubiquitin-proteasome system, providing a mechanistic link between synaptic activity, protein turnover and the functional reorganization of synapses.}, Author = {M. D. Ehlers}, Journal = {Nat Neurosci}, Month = {Mar}, Number = {3}, Pages = {231-42}, Title = {{Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system.}}, Volume = {6}, Year = {2003}} @article{Ehrlich2004, Annote = {The regulated delivery of AMPA-type glutamate receptors (AMPARs) to synapses is an important mechanism underlying synaptic plasticity. Here, we ask whether the synaptic scaffolding protein PSD-95 (postsynaptic density 95) participates in AMPAR incorporation during two forms of synaptic plasticity. In hippocampal slice cultures, the expression of PSD-95-green fluorescent protein (PSD-95-GFP) increases AMPAR currents by selectively delivering glutamate receptor 1 (GluR1)-containing receptors to synapses, thus mimicking long-term potentiation (LTP). Mutational analysis shows that the N terminal of PSD-95 including the first two PDZ [PSD-95/Discs large (Dlg)/zona occludens-1 (ZO-1)] domains is necessary and sufficient to mediate this effect. Further supporting a role in synaptic plasticity, wild-type PSD-95 occludes LTP and dominant negative forms block LTP. Moreover, we demonstrate that PSD-95 also participates in AMPAR delivery during experience-driven plasticity in vivo. In the barrel cortex from experience-deprived animals, the expression of PSD-95-GFP selectively increases AMPAR currents, mimicking experience-driven plasticity. In nondeprived animals, PSD-95-GFP produces no additional potentiation, indicating common mechanisms between PSD-95-mediated potentiation and experience-driven synaptic strengthening. A dominant negative form of PSD-95 blocks experience-driven potentiation of synapses. Pharmacological analysis in slice cultures reveals that PSD-95 acts downstream of other signaling pathways involved in LTP. We conclude that PSD-95 controls activity-dependent AMPAR incorporation at synapses via PDZ interactions not only during LTP in vitro but also during experience-driven synaptic strengthening by natural stimuli in vivo.}, Author = {I. Ehrlich and R. Malinow}, Journal = {J Neurosci}, Month = {Jan}, Number = {4}, Pages = {916-27}, Title = {{Postsynaptic density 95 controls AMPA receptor incorporation during long-term potentiation and experience-driven synaptic plasticity.}}, Volume = {24}, Year = {2004}} @article{El-Husseini2000b, Annote = {Postsynaptic density-95 (PSD-95/SAP-90) is a palmitoylated peripheral membrane protein that scaffolds ion channels at excitatory synapses. To elucidate mechanisms for postsynaptic ion channel clustering, we analyzed the cellular trafficking of PSD-95. We find that PSD-95 transiently associates with a perinuclear membranous compartment and traffics with vesiculotubular structures, which migrate in a microtubule-dependent manner. Trafficking of PSD-95 with these vesiculotubular structures requires dual palmitoylation, which is specified by five consecutive hydrophobic residues at the NH(2) terminus. Mutations that disrupt dual palmitoylation of PSD-95 block both ion channel clustering by PSD-95 and its synaptic targeting. Replacing the palmitoylated NH(2) terminus of PSD-95 with alternative palmitoylation motifs at either the NH(2) or COOH termini restores ion channel clustering also induces postsynaptic targeting, respectively. In brain, we find that PSD-95 occurs not only at PSDs but also in association with intracellular smooth tubular structures in dendrites and spines. These data imply that PSD-95 is an itinerant vesicular protein; initial targeting of PSD-95 to an intracellular membrane compartment may participate in postsynaptic ion channel clustering by PSD-95.}, Author = {A. E. El-Husseini and S. E. Craven and D. M. Chetkovich and B. L. Firestein and E. Schnell and C. Aoki and D. S. Bredt}, Journal = {J Cell Biol}, Month = {Jan}, Number = {1}, Pages = {159-72}, Title = {{Dual palmitoylation of PSD-95 mediates its vesiculotubular sorting, postsynaptic targeting, and ion channel clustering.}}, Volume = {148}, Year = {2000}} @article{El-Husseini2000, Annote = {PSD-95 is a neuronal PDZ protein that associates with receptors and cytoskeletal elements at synapses, but whose function is uncertain. We found that overexpression of PSD-95 in hippocampal neurons can drive maturation of glutamatergic synapses. PSD-95 expression enhanced postsynaptic clustering and activity of glutamate receptors. Postsynaptic expression of PSD-95 also enhanced maturation of the presynaptic terminal. These effects required synaptic clustering of PSD-95 but did not rely on its guanylate kinase domain. PSD-95 expression also increased the number and size of dendritic spines. These results demonstrate that PSD-95 can orchestrate synaptic development and are suggestive of roles for PSD-95 in synapse stabilization and plasticity.}, Author = {A. E. El-Husseini and E. Schnell and D. M. Chetkovich and R. A. Nicoll and D. S. Bredt}, Journal = {Science}, Month = {Nov}, Number = {5495}, Pages = {1364-1368}, Title = {{PSD-95 involvement in maturation of excitatory synapses.}}, Volume = {290}, Year = {2000}} @article{Engert1999, Annote = {Long-term enhancement of synaptic efficacy in the hippocampus is an important model for studying the cellular mechanisms of neuronal plasticity, circuit reorganization, and even learning and memory. Although these long-lasting functional changes are easy to induce, it has been very difficult to demonstrate that they are accompanied or even caused by morphological changes on the subcellular level. Here we combined a local superfusion technique with two-photon imaging, which allowed us to scrutinize specific regions of the postsynaptic dendrite where we knew that the synaptic changes had to occur. We show that after induction of long-lasting (but not short-lasting) functional enhancement of synapses in area CA1, new spines appear on the postsynaptic dendrite, whereas in control regions on the same dendrite or in slices where long-term potentiation was blocked, no significant spine growth occurred.}, Author = {F. Engert and T. Bonhoeffer}, Journal = {Nature}, Month = {May}, Number = {6731}, Pages = {66-70}, Title = {{Dendritic spine changes associated with hippocampal long-term synaptic plasticity.}}, Volume = {399}, Year = {1999}} @article{Engert1997, Annote = {Long-term potentiation (LTP), the long-lasting increase in synaptic transmission, has been proposed to be a cellular mechanism essential for learning and memory, neuronal development, and circuit reorganization. In the original theoretical and experimental work it was assumed that only synapses that had experienced concurrent pre- and postsynaptic activity are subject to synaptic modification. It has since been shown, however, that LTP is also expressed in synapses on neighbouring neurons that have not undergone the induction procedure. Yet, it is still believed that this spread of LTP is limited to adjacent postsynaptic cells, and does not occur for synapses on neighbouring input fibres. However, for technical reasons, tests for 'input specificity' were always done for synapses relatively far apart. Here we have used a new local superfusion technique, which allowed us to assess the synaptic specificity of LTP with a spatial resolution of approximately 30 microm. Our results indicate that there is no input specificity at a distance of less than 70 microm. Synapses in close proximity to a site of potentiation are also potentiated regardless of their own history of activation, whereas synapses far away show no potentiation.}, Author = {F. Engert and T. Bonhoeffer}, Journal = {Nature}, Month = {Jul}, Number = {6639}, Pages = {279-84}, Title = {{Synapse specificity of long-term potentiation breaks down at short distances.}}, Volume = {388}, Year = {1997}} @article{English1997, Annote = {The mitogen-activated protein kinase (MAPK) cascade has been intensely studied as a primary biochemical pathway through which a variety of extracellular stimuli initiate and regulate processes of cellular transformation. That MAPKs are abundantly expressed in postmitotic neurons, however, suggests different yet currently unknown functions for this cascade in the mature nervous system. Here we report that the MAPK cascade is required for hippocampal long term potentiation (LTP), a robust and widely studied form of synaptic plasticity. We observed that PD 098059, a selective inhibitor of the MAPK cascade, blocked MAPK activation in response to direct stimulation of the NMDA receptor as well as to LTP-inducing stimuli. Furthermore, inhibition of the MAPK cascade markedly attenuated the induction of LTP. PD 098059, however, had no effect on the expression of established LTP, and the MAPK cascade was not persistently activated during LTP expression. Our observations provide the first demonstration of a role for the MAPK cascade in the activity-dependent modification of synaptic connections between neurons in the adult mammalian nervous system.}, Author = {J. D. English and J. D. Sweatt}, Journal = {J Biol Chem}, Month = {Aug}, Number = {31}, Pages = {19103-19106}, Title = {{A requirement for the mitogen-activated protein kinase cascade in hippocampal long term potentiation.}}, Volume = {272}, Year = {1997}} @article{English1996, Annote = {Although classically studied as regulators of cell proliferation and differentiation, mitogen-activated protein kinases (MAPKs) are highly expressed in post-mitotic neurons of the adult nervous system. We have begun investigating the potential role of MAPKs in the regulation of synaptic plasticity in mature neurons. In particular, we have studied the regulation of two MAPK isoforms, p44 and p42 MAPK, in hippocampal long term potentiation (LTP), a system widely studied as a model for the cellular basis of learning and memory. We have found that p42 MAPK, but not p44 MAPK, is activated in area CA1 following direct stimulation of two required components of the LTP induction cascades: protein kinase C and the N-methyl--aspartate (NMDA) subtype of glutamate receptor. Furthermore, we have demonstrated that p42 MAPK, but not p44 MAPK, is activated in area CA1 in response to LTP-inducing high frequency stimulation and that this activation requires NMDA receptor stimulation. These data demonstrate that p42 MAPK can be regulated in an activity-dependent manner in the hippocampus and identify it as a potential component of the LTP induction cascades in area CA1. Such observations suggest that p42 MAPK might be an important regulator of synaptic plasticity in post-mitotic neurons.}, Author = {J. D. English and J. D. Sweatt}, Journal = {J Biol Chem}, Month = {Oct}, Number = {40}, Pages = {24329-32}, Title = {{Activation of p42 mitogen-activated protein kinase in hippocampal long term potentiation.}}, Volume = {271}, Year = {1996}} @article{Feig1999, Annote = {One of the most powerful ways of studying the function of a protein is to specifically block its activity within cells. Over the past decade, dominant-inhibitory proteins have emerged as popular tools with which to accomplish this task; these mutated proteins interfere with the function of their normal cellular counterparts or with proteins that interact with them. This approach has been used extensively in the elucidation of signal-transduction cascades, such as those involving Ras-family proteins. Here I discuss the power and potential pitfalls of using dominant-inhibitory Ras proteins.}, Author = {L. A. Feig}, Journal = {Nat Cell Biol}, Month = {Jun}, Number = {2}, Pages = {E25-7}, Title = {{Tools of the trade: use of dominant-inhibitory mutants of Ras-family GTPases.}}, Volume = {1}, Year = {1999}} @article{Fiala2002, Author = {J. C. Fiala and B. Allwardt and K. M. Harris}, Journal = {Nat Neurosci}, Keywords = {Kristen Harris}, Month = {Apr}, Number = {4}, Pages = {297-298}, Title = {{Dendritic spines do not split during hippocampal LTP or maturation.}}, Volume = {5}, Year = {2002}} @article{Fiala1998, Annote = {To determine the role of dendritic filopodia in the genesis of excitatory synaptic contacts and dendritic spines in hippocampal area CA1, serial section electron microscopy and three-dimensional analysis of 16 volumes of neuropil from nine male rat pups, aged postnatal day 1 (P1) through P12, were performed. The analysis revealed that numerous dendritic filopodia formed asymmetric synaptic contacts with axons and with filopodia extending from axons, especially during the first postnatal week. At P1, 22 +/- 5.5\% of synapses occurred on dendritic filopodia, with 19 +/- 5.9\% on filopodia at P4, 20 +/- 8.0\% at P6, decreasing to 7.2 +/- 4.7\% at P12 (p < 0.02). Synapses were found at the base and along the entire length of filopodia, with many filopodia exhibiting multiple synaptic contacts. In all, 162 completely traceable dendritic filopodia received 255 asymmetric synaptic contacts. These synapses were found at all parts of filopodia with equal frequency, usually occurring on fusiform swellings of the diameter. Most synaptic contacts (53 +/- 11\%) occurred directly on dendritic shafts during the first postnatal week. A smaller but still substantial portion (32 +/- 12\%) of synapses were on shafts at P12 (p < 0.036). There was a highly significant (p < 0.0002) increase in the proportion of dendritic spine synapses with age, rising from just 4.9 +/- 4.3\% at P1 to 37 +/- 14\% at P12. The concurrence of primarily shaft and filopodial synapses in the first postnatal week suggests that filopodia recruit shaft synapses that later give rise to spines through a process of outgrowth.}, Author = {J. C. Fiala and M. Feinberg and V. Popov and K. M. Harris}, Journal = {J Neurosci}, Keywords = {Kristen Harris}, Month = {Nov}, Number = {21}, Pages = {8900-11}, Title = {{Synaptogenesis via dendritic filopodia in developing hippocampal area CA1.}}, Volume = {18}, Year = {1998}} @article{Fiala2002b, Annote = {Altered dendritic spines are characteristic of traumatized or diseased brain. Two general categories of spine pathology can be distinguished: pathologies of distribution and pathologies of ultrastructure. Pathologies of spine distribution affect many spines along the dendrites of a neuron and include altered spine numbers, distorted spine shapes, and abnormal loci of spine origin on the neuron. Pathologies of spine ultrastructure involve distortion of subcellular organelles within dendritic spines. Spine distributions are altered on mature neurons following traumatic lesions, and in progressive neurodegeneration involving substantial neuronal loss such as in Alzheimer's disease and in Creutzfeldt-Jakob disease. Similarly, spine distributions are altered in the developing brain following malnutrition, alcohol or toxin exposure, infection, and in a large number of genetic disorders that result in mental retardation, such as Down's and fragile-X syndromes. An important question is whether altered dendritic spines are the intrinsic cause of the accompanying neurological disturbances. The data suggest that many categories of spine pathology may result not from intrinsic pathologies of the spiny neurons, but from a compensatory response of these neurons to the loss of excitatory input to dendritic spines. More detailed studies are needed to determine the cause of spine pathology in most disorders and relationship between spine pathology and cognitive deficits.}, Author = {J. C. Fiala and J. Spacek and K. M. Harris}, Journal = {Brain Res Brain Res Rev}, Keywords = {Kristen Harris}, Month = {Jun}, Number = {1}, Pages = {29-54}, Title = {{Dendritic spine pathology: cause or consequence of neurological disorders?}}, Volume = {39}, Year = {2002}} @article{Fischer1998, Annote = {Dendritic spines have been proposed as primary sites of synaptic plasticity in the brain. Consistent with this hypothesis, spines contain high concentrations of actin, suggesting that they might be motile. To investigate this possibility, we made video recordings from hippocampal neurons expressing actin tagged with green fluorescent protein (GFP-actin). This reagent incorporates into actin-containing structures and allows the visualization of actin dynamics in living neurons. In mature neurons, recordings of GFP fluorescence revealed large actin-dependent changes in dendritic spine shape, similar to those inferred from previous studies using fixed tissues. Visible changes occurred within seconds, suggesting that anatomical plasticity at synapses can be extremely rapid. As well as providing a molecular basis for structural plasticity, the presence of motile actin in dendritic spines implicates the postsynaptic element as a primary site of this phenomenon.}, Author = {M. Fischer and S. Kaech and D. Knutti and A. Matus}, Journal = {Neuron}, Keywords = {Matus}, Month = {May}, Number = {5}, Pages = {847-54}, Title = {{Rapid actin-based plasticity in dendritic spines.}}, Volume = {20}, Year = {1998}} @article{Fischer2000, Annote = {Dendritic spines at excitatory synapses undergo rapid, actin-dependent shape changes which may contribute to plasticity in brain circuits. Here we show that actin dynamics in spines are potently inhibited by activation of either AMPA or NMDA subtype glutamate receptors. Activation of either receptor type inhibited actin-based protrusive activity from the spine head. This blockade of motility caused spines to round up so that spine morphology became both more stable and more regular. Inhibition of spine motility by AMPA receptors was dependent on postsynaptic membrane depolarization and influx of Ca 2+ through voltage-activated channels. In combination with previous studies, our results suggest a two-step process in which spines initially formed in response to NMDA receptor activation are subsequently stabilized by AMPA receptors.}, Author = {M. Fischer and S. Kaech and U. Wagner and H. Brinkhaus and A. Matus}, Journal = {Nat Neurosci}, Keywords = {Matus}, Month = {Sep}, Number = {9}, Pages = {887-94}, Title = {{Glutamate receptors regulate actin-based plasticity in dendritic spines.}}, Volume = {3}, Year = {2000}} @article{Gauthier-Campbell2004, Annote = {Although neuronal axons and dendrites with their associated filopodia and spines exhibit a profound cell polarity, the mechanism by which they develop is largely unknown. Here, we demonstrate that specific palmitoylated protein motifs, characterized by two adjacent cysteines and nearby basic residues, are sufficient to induce filopodial extensions in heterologous cells and to increase the number of filopodia and the branching of dendrites and axons in neurons. Such motifs are present at the N-terminus of GAP-43 and the C-terminus of paralemmin, two neuronal proteins implicated in cytoskeletal organization and filopodial outgrowth. Filopodia induction is blocked by mutations of the palmitoylated sites or by treatment with 2-bromopalmitate, an agent that inhibits protein palmitoylation. Moreover, overexpression of a constitutively active form of ARF-6, a GTPase that regulates membrane cycling and dendritic branching reversed the effects of the acylated protein motifs. Filopodia induction by the specific palmitoylated motifs was also reduced upon overexpression of a dominant negative form of the GTPase cdc42. These results demonstrate that select dually lipidated protein motifs trigger changes in the development and growth of neuronal processes.}, Author = {C. Gauthier-Campbell and D. S. Bredt and T. H. Murphy and A. E. El-Husseini}, Journal = {Mol Biol Cell}, Month = {Feb}, Title = {{Regulation of dendritic branching and filopodia formation in hippocampal neurons by specific acylated protein motifs.}}, Year = {2004}} @article{Grant2001, Annote = {Synaptic transmission of distinct patterns of spikes, or 'neural code', leads to plastic changes in synapses and other parts of the neuron, as well as learning in animals. Recent findings indicate that specialized multiprotein structures associated with neurotransmitter receptors and cell-adhesion proteins function as molecular devices that both read the neural code and initiate long-term changes in synaptic structure and function.}, Author = {S. G. Grant and T. J. O'Dell}, Journal = {Curr Opin Neurobiol}, Month = {Jun}, Number = {3}, Pages = {363-368}, Title = {{Multiprotein complex signaling and the plasticity problem.}}, Volume = {11}, Year = {2001}} @article{Hall1998, Annote = {The actin cytoskeleton mediates a variety of essential biological functions in all eukaryotic cells. In addition to providing a structural framework around which cell shape and polarity are defined, its dynamic properties provide the driving force for cells to move and to divide. Understanding the biochemical mechanisms that control the organization of actin is thus a major goal of contemporary cell biology, with implications for health and disease. Members of the Rho family of small guanosine triphosphatases have emerged as key regulators of the actin cytoskeleton, and furthermore, through their interaction with multiple target proteins, they ensure coordinated control of other cellular activities such as gene transcription and adhesion.}, Author = {A. Hall}, Journal = {Science}, Month = {Jan}, Number = {5350}, Pages = {509-14}, Title = {{Rho GTPases and the actin cytoskeleton.}}, Volume = {279}, Year = {1998}} @article{Harris1999, Annote = {Dendritic spines are distinguished by their shapes, subcellular composition, and synaptic receptor subtypes. Recent studies show that actin-dependent movements take place in spine heads, that spines emerge from stubby and shaft synapses after dendritic filopodia disappear, and that spines can form without synaptic activation, are maintained by optimal activation, and are lost with excessive activation or during degeneration.}, Author = {K. M. Harris}, Journal = {Curr Opin Neurobiol}, Keywords = {review}, Month = {Jun}, Number = {3}, Pages = {343-348}, Title = {{Structure, development, and plasticity of dendritic spines.}}, Volume = {9}, Year = {1999}} @article{Harris2003, Annote = {Two key hypotheses about the structural basis of long-term potentiation (LTP) are evaluated in light of new findings from immature rat hippocampal slices. First, it is shown why dendritic spines do not split during LTP. Instead a small number of spine-like dendritic protrusions may emerge to enhance connectivity with potentiated axons. These 'same dendrite multiple synapse boutons' provide less than a 3\% increase in connectivity and do not account for all of LTP or memory, as they do not accumulate during maturation. Second, polyribosomes in dendritic spines served to identify which of the existing synapses enlarged to sustain more than a 30\% increase in synaptic strength. Thus, both enhanced connectivity and enlarged synapses result during LTP, with synapse enlargement being the greater effect.}, Author = {K. M. Harris and J. C. Fiala and L. Ostroff}, Journal = {Philos Trans R Soc Lond B Biol Sci}, Keywords = {Kristen Harris, review}, Month = {Apr}, Number = {1432}, Pages = {745-748}, Title = {{Structural changes at dendritic spine synapses during long-term potentiation.}}, Volume = {358}, Year = {2003}} @article{Harris1994, Author = {K. M. Harris and S. B. Kater}, Journal = {Annu Rev Neurosci}, Keywords = {review}, Pages = {341-71}, Title = {{Dendritic spines: cellular specializations imparting both stability and flexibility to synaptic function.}}, Volume = {17}, Year = {1994}} @article{Hashimoto2003, Annote = {The neuroprotective effects of lithium, a mood stabilizer, against glutamate-induced excitotoxicity in rat cortical neurons were associated with a decrease in Tyr1472 phosphorylation of the N-methyl-D-aspartate (NMDA) receptor NR2B subunit and a loss of receptor activity. Since this receptor tyrosine phosphorylation is mediated by the Src-family tyrosine kinases, we investigated the effects of lithium on the Src kinase activity. Levels of phosphorylated Src kinase at Tyr416, an index of Src activation, were reduced after treatment with LiCl (1 mM) for more than 3 days. Protein levels of Src-family kinases such as Src, Fyn, and Yes were unchanged by lithium treatment. The activities of cytosolic protein tyrosine kinase and protein phosphatase were also unchanged by lithium treatment, indicating the selectivity and the modulation. Moreover, the levels of postsynaptic densities (PSD) and SynGAP, the scaffolding proteins of the NMDA receptor complex, were unaltered by lithium. A Src kinase inhibitor, SU6656, and an NR2B antagonist, ifenprodil, partially blocked glutamate excitotoxicity. Our results suggest that lithium-induced inactivation of Src kinase contributes to this drug-induced NMDA receptor inhibition and neuroprotection against excitotoxicity.}, Author = {R. Hashimoto and K. Fujimaki and M. R. Jeong and L. Christ and D. M. Chuang}, Journal = {FEBS Lett}, Month = {Mar}, Number = {1-3}, Pages = {145-148}, Title = {{Lithium-induced inhibition of Src tyrosine kinase in rat cerebral cortical neurons: a role in neuroprotection against N-methyl-D-aspartate receptor-mediated excitotoxicity.}}, Volume = {538}, Year = {2003}} @article{Hering2003, Annote = {The number and shape of dendritic spines are influenced by activity and regulated by molecules that organize the actin cytoskeleton of spines. Cortactin is an F-actin binding protein and activator of the Arp2/3 actin nucleation machinery that also interacts with the postsynaptic density (PSD) protein Shank. Cortactin is concentrated in dendritic spines of cultured hippocampal neurons, and the N-terminal half of the protein containing the Arp2/3 and F-actin binding domains is necessary and sufficient for spine targeting. Knockdown of cortactin protein by short-interfering RNA (siRNA) results in depletion of dendritic spines in hippocampal neurons, whereas overexpression of cortactin causes elongation of spines. In response to synaptic stimulation and NMDA receptor activation, cortactin redistributes rapidly from spines to dendritic shaft, correlating with remodeling of the actin cytoskeleton, implicating cortactin in the activity-dependent regulation of spine morphogenesis.}, Author = {H. Hering and M. Sheng}, Journal = {J Neurosci}, Month = {Dec}, Number = {37}, Pages = {11759-69}, Title = {{Activity-dependent redistribution and essential role of cortactin in dendritic spine morphogenesis.}}, Volume = {23}, Year = {2003}} @article{Hsueh1997, Annote = {The PSD-95/SAP90 family of PDZ-containing proteins is directly involved in the clustering of specific ion channels at synapses. We report that channel clustering depends on a conserved N-terminal domain of PSD-95 that mediates multimerization and disulfide linkage of PSD-95 protomers. This N-terminal multimerization domain confers channel clustering activity on a single PDZ domain. Thus, channel clustering depends on aggregation of PDZ domains achieved by head-to-head multimerization of PSD-95, rather than by concatenation of PDZ domains in PSD-95 monomers. This mechanism predicts that PSD-95 can organize heterogeneous membrane protein clusters via differential binding specificities of its three PDZ domains. PSD-95 and its relative chapsyn-110 exist as disulfide-linked complexes in rat brain, consistent with head-to-head multimerization of these proteins in vivo.}, Author = {Y. P. Hsueh and E. Kim and M. Sheng}, Journal = {Neuron}, Month = {May}, Number = {5}, Pages = {803-14}, Title = {{Disulfide-linked head-to-head multimerization in the mechanism of ion channel clustering by PSD-95.}}, Volume = {18}, Year = {1997}} @article{Husi2000, Annote = {N-methyl-d-aspartate receptors (NMDAR) mediate long-lasting changes in synapse strength via downstream signaling pathways. We report proteomic characterization with mass spectrometry and immunoblotting of NMDAR multiprotein complexes (NRC) isolated from mouse brain. The NRC comprised 77 proteins organized into receptor, adaptor, signaling, cytoskeletal and novel proteins, of which 30 are implicated from binding studies and another 19 participate in NMDAR signaling. NMDAR and metabotropic glutamate receptor subtypes were linked to cadherins and L1 cell-adhesion molecules in complexes lacking AMPA receptors. These neurotransmitter-adhesion receptor complexes were bound to kinases, phosphatases, GTPase-activating proteins and Ras with effectors including MAPK pathway components. Several proteins were encoded by activity-dependent genes. Genetic or pharmacological interference with 15 NRC proteins impairs learning and with 22 proteins alters synaptic plasticity in rodents. Mutations in three human genes (NF1, Rsk-2, L1) are associated with learning impairments, indicating the NRC also participates in human cognition.}, Author = {H. Husi and M. A. Ward and J. S. Choudhary and W. P. Blackstock and S. G. Grant}, Journal = {Nat Neurosci}, Month = {Jul}, Number = {7}, Pages = {661-669}, Title = {{Proteomic analysis of NMDA receptor-adhesion protein signaling complexes.}}, Volume = {3}, Year = {2000}} @article{Innocenti1999, Annote = {The Ras-GRF1 exchange factor molecule contains in addition to the catalytic domain two pleckstrin homology (PH1 and PH2), one IQ and one Dbl homology (DH) domains. In this study we investigated the role of such additional domains. We found that a Ras-GRF1 mutant lacking PH1 and IQ domains is sufficient to activate c-fos promoter in response to lysophosphatidic acid (LPA). The same mutant did not increase external stimuli-regulated kinase (ERK) activity, suggesting an additional mechanism for the induction of gene transcription. Isolated DH-PH2 module activates c-Jun NH(2)-terminal kinase and the c-fos promoter in response to LPA, providing the basis for an ERK-independent mechanism. These results provide evidence that Ras-GRF1 acts as a bifunctional molecule on both ERK-dependent and independent pathways.}, Author = {M. Innocenti and R. Zippel and R. Brambilla and E. Sturani}, Journal = {FEBS Lett}, Month = {Oct}, Number = {2}, Pages = {357-62}, Title = {{CDC25(Mm)/Ras-GRF1 regulates both Ras and Rac signaling pathways.}}, Volume = {460}, Year = {1999}} @article{Isaac2003, Annote = {In this review I discuss the evidence that some glutamatergic synapses exist that lack surface-expressed postsynaptic AMPA receptors (AMPARs) but contain NMDA receptors opposed to a functional release site. I have summarised the electrophysiological, anatomical and cell biological evidence for such postsynaptically silent synapses, and data that support the idea of rapid AMPAR insertion at silent synapses during long-term potentiation (LTP). I also discuss recent findings suggesting that developmental and activity-dependent alteration in the postsynaptic glutamate receptor composition is a general principle that occurs for other receptor subtypes. This review is not intended to provide a full discussion of possible presynaptic mechanisms for silent synapses; these are covered in the accompanying recent article [Voronin and Cherubini (this issue)].}, Author = {J. T. Isaac}, Journal = {Neuropharmacology}, Month = {Sep}, Number = {4}, Pages = {450-60}, Title = {{Postsynaptic silent synapses: evidence and mechanisms.}}, Volume = {45}, Year = {2003}} @article{Kaech1997, Annote = {Dendritic spines contain high concentrations of actin, but neither the isoforms involved nor the mechanism of accumulation is known. In situ hybridization with specific probes established that beta- and gamma-cytoplasmic actins are selectively expressed at high levels by spine-bearing neurons. Transfecting cultured hippocampal neurons with epitope-tagged actin isoforms showed that cytoplasmic beta- and gamma-cytoplasmic actins are correctly targeted to spines, whereas alpha-cardiac muscle actin, which is normally absent from neurons, formed aggregates in dendrites. The transfected actin cDNAs contained only coding domains, suggesting that spine targeting involves amino acid sequences in the proteins, an interpretation supported by experiments with chimeric cDNAs in which C-terminal actin sequences were found to be determinative in spine targeting. By contrast to actin, microtubule components, including tubulin and MAP2, were restricted to the dendritic shaft domain. The close association of cytoplasmic actins with spines together with their general involvement in cell surface motility further supports the idea that actin motility-based changes in spine shape may contribute to synaptic plasticity.}, Author = {S. Kaech and M. Fischer and T. Doll and A. Matus}, Journal = {J Neurosci}, Keywords = {Matus}, Month = {Dec}, Number = {24}, Pages = {9565-72}, Title = {{Isoform specificity in the relationship of actin to dendritic spines.}}, Volume = {17}, Year = {1997}} @article{Kennedy2000b, Author = {M. B. Kennedy}, Journal = {Proc Natl Acad Sci U S A}, Month = {Oct}, Number = {21}, Pages = {11135-11136}, Title = {{Sticking together.}}, Volume = {97}, Year = {2000}} @article{Kennedy2000, Annote = {Dendrites of individual neurons in the vertebrate central nervous system are contacted by thousands of synaptic terminals relaying information about the environment. The postsynaptic membrane at each synaptic terminal is the first place where information is processed as it converges on the dendrite. At the postsynaptic membrane of excitatory synapses, neurotransmitter receptors are attached to large protein "signaling machines" that delicately regulate the strength of synaptic transmission. These machines are visible in the electron microscope and are called the postsynaptic density. By changing synaptic strength in response to neural activity, the postsynaptic density contributes to information processing and the formation of memories.}, Author = {M. B. Kennedy}, Journal = {Science}, Month = {Oct}, Number = {5492}, Pages = {750-754}, Title = {{Signal-processing machines at the postsynaptic density.}}, Volume = {290}, Year = {2000}} @article{Kennedy1999, Author = {M. B. Kennedy}, Journal = {Learn Mem}, Month = {Sep}, Number = {5}, Pages = {417-21}, Title = {{On beyond LTP. Long-term potentiation.}}, Volume = {6}, Year = {1999}} @article{Kennedy1998, Annote = {We have applied techniques from modern molecular biology and biochemistry to unravel the complex molecular structure of the postsynaptic membrane at glutamatergic synapses in the central nervous system. We have characterized a set of new proteins that are constituents of the postsynaptic density, including PSD-95, densin-180, citron (a rho/rac effector protein), and synaptic gp130 Ras GAP (a new Ras GTPase-activating protein). The structure of PSD-95 revealed a new protein motif, the PDZ domain, that plays an important role in the assembly of signal transduction complexes at intercellular junctions. More recently, we have used new imaging tools to observe the dynamics of autophosphorylation of CaM kinase II in intact hippocampal tissue. We have been able to detect changes in the amount of autophosphorylated CaM kinase II in dendrites, individual synapses, and somas of hippocampal neurons following induction of long-term potentiation by tetanic stimulation. In addition, we have observed a specific increase in the concentration of CaM kinase II in dendrites of neurons receiving tetanic stimulation. This increase appears to be the result of dendritic synthesis of new protein. Over the next several years we will apply similar methods to study regulatory changes that occur at the molecular level in glutamatergic synapses in the CNS as the brain processes and stores new information.}, Author = {M. B. Kennedy}, Journal = {Brain Res Brain Res Rev}, Month = {May}, Number = {2-3}, Pages = {243-57}, Title = {{Signal transduction molecules at the glutamatergic postsynaptic membrane.}}, Volume = {26}, Year = {1998}} @article{Kennedy1997, Annote = {The postsynaptic density (PSD) is a tiny, amorphous structure located beneath the postsynaptic membrane of synapses in the CNS. Until recently, the molecular composition and function of the PSD were mostly matters of speculation. With the advent of powerful new microchemical tools and molecular-genetic methods, three new classes of proteins have been identified in the PSD at glutamatergic synapses: the PSD-95 family, the NR2B subunit of the NMDA-type glutamate receptor, and densin-180. The PSD-95 family is involved in clustering of NMDA receptors. NR2B is phosphorylated by Ca2(+)-calmodulin-dependent protein kinase type II, a prominent constituent of the PSD. Densin-180 might represent a new class of synaptic adhesion molecule. Study of these molecules is beginning to reveal the functional significance of the PSD.}, Author = {M. B. Kennedy}, Journal = {Trends Neurosci}, Month = {Jun}, Number = {6}, Pages = {264-268}, Title = {{The postsynaptic density at glutamatergic synapses.}}, Volume = {20}, Year = {1997}} @article{Kennedy2001, Author = {M. B. Kennedy and P. Manzerra}, Journal = {Proc Natl Acad Sci U S A}, Month = {Oct}, Number = {22}, Pages = {12323-12324}, Title = {{Telling tails.}}, Volume = {98}, Year = {2001}} @article{Kim2003, Annote = {Synaptic GTPase-activating protein (SynGAP) is a neuronal RasGAP (Ras GTPase-activating protein) that is selectively expressed in brain and highly enriched at excitatory synapses, where it negatively regulates Ras activity and its downstream signaling pathways. To investigate the physiological role of SynGAP in the brain, we have generated mutant mice lacking the SynGAP protein. These mice exhibit postnatal lethality, indicating that SynGAP plays a critical role during neuronal development. In addition, cell biological experiments show that neuronal cultures from mutant mice have more synaptic AMPA receptor clusters, suggesting that SynGAP regulates glutamate receptor synaptic targeting. Moreover, electrophysiological studies demonstrated that heterozygous mutant mice have a specific defect in hippocampal long-term potentiation (LTP). These studies show that the regulation of synaptic Ras signaling by SynGAP is important for proper neuronal development and glutamate receptor trafficking and is critical for the induction of LTP.}, Author = {J. H. Kim and H. K. Lee and K. Takamiya and R. L. Huganir}, Journal = {J Neurosci}, Month = {Feb}, Number = {4}, Pages = {1119-24}, Title = {{The role of synaptic GTPase-activating protein in neuronal development and synaptic plasticity.}}, Volume = {23}, Year = {2003}} @article{Kim1998, Annote = {The PSD-95/SAP90 family of proteins has recently been implicated in the organization of synaptic structure. Here, we describe the isolation of a novel Ras-GTPase activating protein, SynGAP, that interacts with the PDZ domains of PSD-95 and SAP102 in vitro and in vivo. SynGAP is selectively expressed in brain and is highly enriched at excitatory synapses, where it is present in a large macromolecular complex with PSD-95 and the NMDA receptor. SynGAP stimulates the GTPase activity of Ras, suggesting that it negatively regulates Ras activity at excitatory synapses. Ras signaling at the postsynaptic membrane may be involved in the modulation of excitatory synaptic transmission by NMDA receptors and neurotrophins. These results indicate that SynGAP may play an important role in the modulation of synaptic plasticity.}, Author = {J. H. Kim and D. Liao and L. F. Lau and R. L. Huganir}, Journal = {Neuron}, Month = {Apr}, Number = {4}, Pages = {683-91}, Title = {{SynGAP: a synaptic RasGAP that associates with the PSD-95/SAP90 protein family.}}, Volume = {20}, Year = {1998}} @article{Kirov1999, Annote = {Dendrites of CA1 pyramidal neurons in mature rat hippocampal slices were exposed to different levels of synaptic activation. In some slices, synaptic transmission was blocked with glutamate receptor antagonists, sodium and calcium channel blockers and/or a nominally calcium-free medium with high magnesium. In other slices, synapses were activated with low-frequency control stimulation or repeated tetanic stimulation. In slices with blocked synaptic transmission, dendrites were spinier than in either of the activated states. Thus, mature neurons can increase their numbers of spines, possibly compensating for lost synaptic activity.}, Author = {S. A. Kirov and K. M. Harris}, Journal = {Nat Neurosci}, Keywords = {Kristen Harris}, Month = {Oct}, Number = {10}, Pages = {878-83}, Title = {{Dendrites are more spiny on mature hippocampal neurons when synapses are inactivated.}}, Volume = {2}, Year = {1999}} @article{Kodaki1994, Annote = {BACKGROUND: Activation of the mammalian phosphatidylinositol 3-kinase complex can play a critical role in transducing growth factor responses. The lipid kinase complex, which is made up of p85 alpha and p110 alpha regulatory and catalytic subunits, becomes associated with a number of activated receptor protein tyrosine kinases, but the mechanism of its activation has not yet been defined. Recent evidence indicates that Ras can bind to the p85 alpha/p110 alpha complex. We describe here the functional regulation of the mammalian phosphatidylinositol 3-kinase complex by Ras. RESULTS: Expression of p110 alpha, the catalytic subunit of phosphatidylinositol 3-kinase, in the fission yeast, Schizosaccharomyces pombe, has been used to demonstrate an inhibitory effect of p85 alpha on p110 alpha activity in intact cells; inhibition did not result from a decrease in p110 alpha expression. In this cellular context, we have investigated the effect of a constitutively active mutant of Ras, v-Ras, either on p85 alpha or p110 alpha-alone, or on the p85 alpha/p110 alpha complex. In the presence of the p85 alpha/p110 alpha complex, v-Ras suppressed cell growth, but an effector-domain mutant of v-Ras did not. The growth-suppressive effect of v-Ras was not seen for any other combination of expressed proteins. The phenotype induced by v-Ras was consistent with activation of the p85 alpha/p110 alpha complex: it was sensitive to the phosphatidylinositol 3-kinase inhibitor, wortmannin, and the cells accumulated 3-phosphorylated polyphosphoinositides. Activation of purified p85 alpha/p110 alpha by purified recombinant Ras in vitro was also demonstrated. CONCLUSIONS: The phosphatidylinositol 3-kinase complex, p85 alpha/p110 alpha, shows a suppressed catalytic function in vivo when compared with free p110 alpha. This complex can, however, be activated by Ras. We suggest that the phosphatidylinositol 3-kinase p85 alpha/p110 alpha complex is a downstream effector of Ras.}, Author = {T. Kodaki and R. Woscholski and B. Hallberg and P. Rodriguez-Viciana and J. Downward and P. J. Parker}, Journal = {Curr Biol}, Month = {Sep}, Number = {9}, Pages = {798-806}, Title = {{The activation of phosphatidylinositol 3-kinase by Ras.}}, Volume = {4}, Year = {1994}} @article{Komiyama2002, Annote = {At excitatory synapses, the postsynaptic scaffolding protein postsynaptic density 95 (PSD-95) couples NMDA receptors (NMDARs) to the Ras GTPase-activating protein SynGAP. The close association of SynGAP and NMDARs suggests that SynGAP may have an important role in NMDAR-dependent activation of Ras signaling pathways, such as the MAP kinase pathway, and in synaptic plasticity. To explore this issue, we examined long-term potentiation (LTP), p42 MAPK (ERK2) signaling, and spatial learning in mice with a heterozygous null mutation of the SynGAP gene (SynGAP(-/+)). In SynGAP(-/+) mutant mice, the induction of LTP in the hippocampal CA1 region was strongly reduced in the absence of any detectable alteration in basal synaptic transmission and NMDAR-mediated synaptic currents. Although basal levels of activated ERK2 were elevated in hippocampal extracts from SynGAP(-/+) mice, NMDAR stimulation still induced a robust increase in ERK activation in slices from SynGAP(-/+) mice. Thus, although SynGAP may regulate the ERK pathway, its role in LTP most likely involves additional downstream targets. Consistent with this, the amount of potentiation induced by stimulation protocols that induce an ERK-independent form of LTP were also significantly reduced in slices from SynGAP(-/+) mice. An elevation of basal phospho-ERK2 levels and LTP deficits were also observed in SynGAP(-/+)/H-Ras(-)/- double mutants, suggesting that SynGAP may normally regulate Ras isoforms other than H-Ras. A comparison of SynGAP and PSD-95 mutants suggests that PSD-95 couples NMDARs to multiple downstream signaling pathways with very different roles in LTP and learning.}, Author = {N. H. Komiyama and A. M. Watabe and H. J. Carlisle and K. Porter and P. Charlesworth and J. Monti and D. J. Strathdee and C. M. O'Carroll and S. J. Martin and R. G. Morris and T. J. O'Dell and S. G. Grant}, Journal = {J Neurosci}, Month = {Nov}, Number = {22}, Pages = {9721-32}, Title = {{SynGAP regulates ERK/MAPK signaling, synaptic plasticity, and learning in the complex with postsynaptic density 95 and NMDA receptor.}}, Volume = {22}, Year = {2002}} @article{Kramer1984, Annote = {The efficiency of methyl-directed DNA mismatch-repair of E. coli acting in vivo on heteroduplex genomes of phage M13 was found to be strongly dependent on the nature of the base/base mismatch to be corrected. Three efficiency classes were characterized:high (T/G, C/A and G/G); intermediate (A/A); and low (G/A, A/G, T/T, C/C, C/T and T/C). Methyl-directed DNA mismatch repair was lost completely for any type of mismatch in strains carrying either mutL or mutS mutations. Data obtained with a mutH mutant suggest that this locus is involved in methyl-dependent DNA strand discrimination. A functional correlation is suggested between the differential repair efficiencies and the frequencies of the corresponding replication errors.}, Author = {B. Kramer and W. Kramer and H. J. Fritz}, Journal = {Cell}, Month = {Oct}, Number = {3}, Pages = {879-87}, Title = {{Different base/base mismatches are corrected with different efficiencies by the methyl-directed DNA mismatch-repair system of E. coli.}}, Volume = {38}, Year = {1984}} @article{Krapivinsky2003, Annote = {The NMDA subtype of glutamate receptors (NMDAR) at excitatory neuronal synapses plays a key role in synaptic plasticity. The extracellular signal-regulated kinase (ERK1,2 or ERK) pathway is an essential component of NMDAR signal transduction controlling the neuroplasticity underlying memory processes, neuronal development, and refinement of synaptic connections. Here we show that NR2B, but not NR2A or NR1 subunits of the NMDAR, interacts in vivo and in vitro with RasGRF1, a Ca(2+)/calmodulin-dependent Ras-guanine-nucleotide-releasing factor. Specific disruption of this interaction in living neurons abrogates NMDAR-dependent ERK activation. Thus, RasGRF1 serves as NMDAR-dependent regulator of the ERK kinase pathway. The specific association of RasGRF1 with the NR2B subunit and study of ERK activation in neurons with varied content of NR2B suggests that NR2B-containing channels are the dominant activators of the NMDA-dependent ERK pathway.}, Author = {G. Krapivinsky and L. Krapivinsky and Y. Manasian and A. Ivanov and R. Tyzio and C. Pellegrino and Y. Ben-Ari and D. E. Clapham and I. Medina}, Journal = {Neuron}, Month = {Nov}, Number = {4}, Pages = {775-84}, Title = {{The NMDA receptor is coupled to the ERK pathway by a direct interaction between NR2B and RasGRF1.}}, Volume = {40}, Year = {2003}} @article{Lemmon2002, Annote = {Pleckstrin homology (PH) domains are 100-120 amino acid protein modules best known for their ability to bind phosphoinositides. All possess an identical core beta-sandwich fold and display marked electrostatic sidedness. The binding site for phosphoinositides lies in the center of the positively charged face. In some cases this binding site is well defined, allowing highly specific and strong ligand binding. In several of these cases the PH domains specifically recognize 3-phosphorylated phosphoinositides, allowing them to drive membrane recruitment in response to phosphatidylinositol 3-kinase activation. Examples of these PH domain-containing proteins include certain Dbl family guanine nucleotide exchange factors, protein kinase B, PhdA, and pleckstrin-2. PH domain-mediated membrane recruitment of these proteins contributes to regulated actin assembly and cell polarization. Many other PH domain-containing cytoskeletal proteins, such as spectrin, have PH domains that bind weakly, and to all phosphoinositides. In these cases, the individual phosphoinositide interactions may not be sufficient for membrane association, but appear to require self-assembly of their host protein and/or cooperation with other anchoring motifs within the same molecule to drive membrane attachment.}, Author = {M. A. Lemmon and K. M. Ferguson and C. S. Abrams}, Journal = {FEBS Lett}, Month = {Feb}, Number = {1}, Pages = {71-76}, Title = {{Pleckstrin homology domains and the cytoskeleton.}}, Volume = {513}, Year = {2002}} @article{Li2001, Annote = {We cloned a cDNA encoding a novel synGAP, synGAP-d (GenBank(TM) accession number ), from a rat brain cDNA library. The clone consisted of 4801 nucleotides with a coding sequence of 3501 nucleotides, encoded a protein consisting of 1166 amino acids with >99\% homology with 1092 amino acid overlaps to synGAP, and contained a 13-nucleotide insertion to the previously reported synGAP mRNAs, which suggested that the clone was a splice variant of synGAP. We also found that there are at least seven variants in the 3' portion of the synGAP mRNA and that they encoded five different protein isoforms. The coding sequence of these C-terminal variants were classified into alpha1, alpha2, beta1, beta2, beta3, beta4, and gamma, and synGAP-d was classified as the beta1 form. The previously reported synGAPs (synGAP-a, -b, and -c and p135synGAP) can be classified as the alpha1 isoform. All isoforms were expressed specifically in the brain. Unexpectedly, the beta isoform, which lacks a C-terminal PSD-95-binding motif ((S/T)XV), was more restricted to the postsynaptic density fraction than the motif-containing alpha1 isoform. The beta isoform did not interact with PSD-95 but specifically interacted with a nonphosphorylated alpha subunit of Ca(2+)/calmodulin-dependent protein kinase II through its unique C-terminal tail.}, Author = {W. Li and A. Okano and Q. B. Tian and K. Nakayama and T. Furihata and H. Nawa and T. Suzuki}, Journal = {J Biol Chem}, Month = {Jun}, Number = {24}, Pages = {21417-24}, Title = {{Characterization of a novel synGAP isoform, synGAP-beta.}}, Volume = {276}, Year = {2001}} @article{Li2003, Author = {Z. Li and M. Sheng}, Journal = {Nat Rev Mol Cell Biol}, Month = {Nov}, Number = {11}, Pages = {833-41}, Title = {{Some assembly required: the development of neuronal synapses.}}, Volume = {4}, Year = {2003}} @article{Liao2001, Annote = {Many recent studies have shown that excitatory synapses can contain NMDA receptor responses in the absence of functional AMPA receptors and are therefore postsynaptically silent at resting membrane potentials. The activation of silent synapses via the rapid acquisition of AMPA receptor responses may be important in synaptic plasticity and neuronal development. Our recent immunocytochemical studies that used cultured hippocampal neurons have provided evidence for "morphological silent synapses" that physically contain NMDA receptors but no AMPA receptors. Here we show that the activation of NMDA receptors by spontaneous synaptic activity results in the rapid recruitment of AMPA receptors into these morphological silent synapses within minutes. In parallel, we find a significant increase in the frequency of AMPA receptor-mediated miniature EPSCs (mEPSCs). NMDA receptor activation also results in a mobilization of calcium/calmodulin (CaM) kinase II to synapses and an increase in the phosphorylation of surface AMPA receptors on the major CaM kinase II phosphorylation site. These results demonstrate that AMPA receptors can be modified and recruited rapidly to silent synapses via the activation of NMDA receptors by spontaneous synaptic activity.}, Author = {D. Liao and R. H. Scannevin and R. Huganir}, Journal = {J Neurosci}, Month = {Aug}, Number = {16}, Pages = {6008-17}, Title = {{Activation of silent synapses by rapid activity-dependent synaptic recruitment of AMPA receptors.}}, Volume = {21}, Year = {2001}} @article{Liao1999, Annote = {Many excitatory synapses are thought to be postsynaptically 'silent', possessing functional NMDA but lacking functional AMPA glutamate receptors. The acquisition of AMPA receptors at silent synapses may be important in synaptic plasticity and neuronal development. Here we characterize a possible morphological correlate of silent synapses in cultured hippocampal neurons. Initially, most excitatory synapses contained NMDA receptors, but only a few contained detectable AMPA receptors. Synapses progressively acquired AMPA receptors as the cultures matured. AMPA receptor blockade increased the number, size and fluorescent intensity of AMPA receptor clusters and rapidly induced the appearance of AMPA receptors at 'silent' synapses. In contrast, NMDA receptor blockade increased the size, intensity and number of NMDA receptor clusters and decreased the number of AMPA receptor clusters, resulting in an increase in the proportion of 'silent' synapses. These results suggest that the number of silent synapses is regulated during development and by changes in synaptic activity.}, Author = {D. Liao and X. Zhang and R. O'Brien and M. D. Ehlers and R. L. Huganir}, Journal = {Nat Neurosci}, Keywords = {Huganir}, Month = {Jan}, Number = {1}, Pages = {37-43}, Title = {{Regulation of morphological postsynaptic silent synapses in developing hippocampal neurons.}}, Volume = {2}, Year = {1999}} @article{Lim2003, Annote = {PSD-95 binds to and co-localizes with NMDA receptors at postsynaptic sites. Their co-expression in COS7 cells induces the formation of aggregates containing both proteins. These findings have lead to the hypothesis that PSD-95 helps to cluster NMDA receptors at postsynaptic sites. In addition, PSD-95 binds various regulatory proteins including Src, Pyk2, SynGAP, and nNOS and may recruit signaling proteins to NMDA receptors. We tested whether synaptic transmission or plasticity was affected by acute dissociation of the PSD-95-NMDA receptor interaction with various peptides that bound to the first two PDZ domains of PSD-95 and its homologs and with antibodies directed against the very C-terminus of the NR2A and NR2B subunits of the NMDA receptor. Membrane-impermeable peptides injected via whole cell patch electrodes distributed within minutes throughout dendritic branches into spines in acute hippocampal slices and membrane-permeable peptides containing 11 arginine residues effectively accumulated in neurites in slices and primary hippocampal cultures. Neither peptides nor antibodies showed any effect on basal synaptic transmission or induction of long-term potentiation (LTP) in hippocampal slices. Pharmacologically isolated NMDA receptor activity was also not affected. However, the membrane-permeable peptide disrupted the NMDA receptor-PSD-95 interaction in slices as tested by immunoprecipitation and subsequent immunoblotting. These findings suggest that acute dissociation of PSD-95 and its homologs from the NMDA receptor and likely from other protein complexes does not result in any easily detectable physiological effects in hippocampal slices. However, we cannot exclude a role of PSD-95 in early events that lead to clustering of NMDA receptors or of other proteins including stargazin and AMPA receptors at postsynaptic sites nor do these experiments address the possibility of long-term changes in the slices. In fact, incubation of primary hippocampal cultures with the membrane-permeable peptide lead to a moderate decrease in the number of dendritic clusters of PSD-95 and NMDA receptors and their colocalization by 20-30\%, suggesting some role of PSD-95 and its homologs in NMDA receptor clustering.}, Author = {I. A. Lim and M. A. Merrill and Y. Chen and J. W. Hell}, Journal = {Neuropharmacology}, Month = {Nov}, Number = {6}, Pages = {738-54}, Title = {{Disruption of the NMDA receptor-PSD-95 interaction in hippocampal neurons with no obvious physiological short-term effect.}}, Volume = {45}, Year = {2003}} @article{Lin2004, Annote = {Recent studies have shown that the activation of NMDA receptors can induce rapid changes in dendritic morphology and synaptic recruitment of AMPA receptors in dendritic spines. Here, we analyze the time course of NMDA receptor-induced changes in dendrite morphology and recruitment of AMPA receptors to synapses in cultured neurons. Activation of NMDA receptors causes a rapid transient increase in the size of preexisting spines and then the gradual formation of new dendritic protrusions and spines. NMDA receptor activation also induced GFP-tagged AMPA receptors to cluster in dendrites and to be inserted into the surface of dendritic spines. These results indicate that NMDA receptor activation induces several phases of dendritic plasticity, initial expansion of dendritic spines, followed by the de novo formation of spines and AMPA receptor dendritic clustering and surface expression on spines. Each of these forms of plasticity may have significant effects on the efficacy of synaptic transmission.}, Author = {H. Lin and R. Huganir and D. Liao}, Journal = {Biochem Biophys Res Commun}, Month = {Apr}, Number = {2}, Pages = {501-11}, Title = {{Temporal dynamics of NMDA receptor-induced changes in spine morphology and AMPA receptor recruitment to spines.}}, Volume = {316}, Year = {2004}} @article{Lissin1998, Annote = {Distinct subtypes of glutamate receptors often are colocalized at individual excitatory synapses in the mammalian brain yet appear to subserve distinct functions. To address whether neuronal activity may differentially regulate the surface expression at synapses of two specific subtypes of ionotropic glutamate receptors we epitope-tagged an AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor subunit (GluR1) and an NMDA (N-methyl-D-aspartate) receptor subunit (NR1) on their extracellular termini and expressed these proteins in cultured hippocampal neurons using recombinant adenoviruses. Both receptor subtypes were appropriately targeted to the synaptic plasma membrane as defined by colocalization with the synaptic vesicle protein synaptophysin. Increasing activity in the network of cultured cells by prolonged blockade of inhibitory synapses with the gamma-aminobutyric acid type A receptor antagonist picrotoxin caused an activity-dependent and NMDA receptor-dependent decrease in surface expression of GluR1, but not NR1, at synapses. Consistent with this observation identical treatment of noninfected cultures decreased the contribution of endogenous AMPA receptors to synaptic currents relative to endogenous NMDA receptors. These results indicate that neuronal activity can differentially regulate the surface expression of AMPA and NMDA receptors at individual synapses.}, Author = {D. V. Lissin and S. N. Gomperts and R. C. Carroll and C. W. Christine and D. Kalman and M. Kitamura and S. Hardy and R. A. Nicoll and R. C. Malenka and M. von Zastrow}, Journal = {Proc Natl Acad Sci U S A}, Keywords = {silent synapse}, Month = {Jun}, Number = {12}, Pages = {7097-102}, Title = {{Activity differentially regulates the surface expression of synaptic AMPA and NMDA glutamate receptors.}}, Volume = {95}, Year = {1998}} @article{Luscher2000, Annote = {The biochemical composition of the postsynaptic membrane and the structure of dendritic spines may be rapidly modulated by synaptic activity. Here we review these findings, discuss their implications for long-term potentiation (LTP) and long-term depression (LTD) and propose a model of sequentially occurring expression mechanisms.}, Author = {C. Luscher and R. A. Nicoll and R. C. Malenka and D. Muller}, Journal = {Nat Neurosci}, Keywords = {Malenka}, Month = {Jun}, Number = {6}, Pages = {545-50}, Title = {{Synaptic plasticity and dynamic modulation of the postsynaptic membrane.}}, Volume = {3}, Year = {2000}} @article{Malenka1993, Annote = {Long-term potentiation in the CA1 region of the hippocampus is the most extensively studied model of activity-dependent synaptic plasticity in the mammalian brain. Its induction normally involves activation of postsynaptic N-methyl-D-aspartate (NMDA) receptors, which are thought to control the occurrence of long-term potentiation at individual synapses. Recent work in the hippocampus indicates that NMDA receptor activation does not necessarily lead to induction of long-term potentiation but instead may elicit a repertoire of distinct forms of synaptic plasticity including short-term potentiation or long-term depression. Furthermore, mechanisms exist such that the induction of long-term potentiation can be inhibited by modest activation of NMDA receptors. Experimental results are beginning to clarify the mechanistic relationships between these different phenomena, although much remains unknown. Whatever their underlying mechanisms, these additional forms of NMDA-receptor-dependent synaptic plasticity confer increased flexibility to neural circuits involved in information processing and storage.}, Author = {R. C. Malenka and R. A. Nicoll}, Journal = {Trends Neurosci}, Month = {Dec}, Number = {12}, Pages = {521-527}, Title = {{NMDA-receptor-dependent synaptic plasticity: multiple forms and mechanisms.}}, Volume = {16}, Year = {1993}} @article{Maletic-Savatic1999, Annote = {Activity shapes the structure of neurons and their circuits. Two-photon imaging of CA1 neurons expressing enhanced green fluorescent protein in developing hippocampal slices from rat brains was used to characterize dendritic morphogenesis in response to synaptic activity. High-frequency focal synaptic stimulation induced a period (longer than 30 minutes) of enhanced growth of small filopodia-like protrusions (typically less than 5 micrometers long). Synaptically evoked growth was long-lasting and localized to dendritic regions close (less than 50 micrometers) to the stimulating electrode and was prevented by blockade of N-methyl-D-aspartate receptors. Thus, synaptic activation can produce rapid input-specific changes in dendritic structure. Such persistent structural changes could contribute to the development of neural circuitry.}, Author = {M. Maletic-Savatic and R. Malinow and K. Svoboda}, Journal = {Science}, Keywords = {Malionow R, Svoboda K}, Month = {Mar}, Number = {5409}, Pages = {1923-1927}, Title = {{Rapid dendritic morphogenesis in CA1 hippocampal dendrites induced by synaptic activity.}}, Volume = {283}, Year = {1999}} @article{Malinow2003, Annote = {Activity-dependent changes in synaptic function are believed to underlie the formation of memories. A prominent example is long-term potentiation (LTP), whose mechanisms have been the subject of considerable scrutiny over the past few decades. I review studies from our laboratory that support a critical role for AMPA receptor trafficking in LTP and experience-dependent plasticity.}, Author = {R. Malinow}, Journal = {Philos Trans R Soc Lond B Biol Sci}, Month = {Apr}, Number = {1432}, Pages = {707-14}, Title = {{AMPA receptor trafficking and long-term potentiation.}}, Volume = {358}, Year = {2003}} @article{Malinow2002, Annote = {Activity-dependent changes in synaptic function are believed to underlie the formation of memories. Two prominent examples are long-term potentiation (LTP) and long-term depression (LTD), whose mechanisms have been the subject of considerable scrutiny over the past few decades. Here we review the growing literature that supports a critical role for AMPA receptor trafficking in LTP and LTD, focusing on the roles proposed for specific AMPA receptor subunits and their interacting proteins. While much work remains to understand the molecular basis for synaptic plasticity, recent results on AMPA receptor trafficking provide a clear conceptual framework for future studies.}, Author = {R. Malinow and R. C. Malenka}, Journal = {Annu Rev Neurosci}, Pages = {103-26}, Title = {{AMPA receptor trafficking and synaptic plasticity.}}, Volume = {25}, Year = {2002}} @article{Marcora2003, Abstract = {NeuroD (ND) is a basic helix-loop-helix transcription factor important for neuronal development and survival. By using a yeast two-hybrid screen, we identified two proteins that interact with ND, huntingtin-associated protein 1 (HAP1) and mixed-lineage kinase 2 (MLK2), both of which are known to interact with huntingtin (Htt). Htt is a ubiquitous protein important for neuronal transcription, development, and survival, and loss of its function has been implicated in the pathogenesis of Huntington's disease, a neurodegenerative disorder. However, the mechanism by which Htt exerts its neuron-specific function at the molecular level is unknown. Here we report that Htt interacts with ND via HAP1, and that MLK2 phosphorylates and stimulates the activity of ND. Furthermore, we show that Htt and HAP1 facilitate the activation of ND by MLK2. To our knowledge, ND is the first example of a neuron-specific transcription factor involved in neuronal development and survival whose activity is modulated by Htt. We propose that Htt, together with HAP1, may function as a scaffold for the activation of ND by MLK2.}, Author = {Edoardo Marcora and Katherine Gowan and Jacqueline E Lee}, Doi = {10.1073/pnas.1133382100}, Journal = {Proc Natl Acad Sci U S A}, Keywords = {Alkaline Phosphatase, Animals, Carbon-Oxygen Lyases, Cell Survival, DNA, DNA, Complementary, DNA-(Apurinic or Apyrimidinic Site) Lyase, Gene Deletion, Human, Huntington Disease, MAP Kinase Kinase Kinases, Mice, Models, Biological, Nerve Tissue Proteins, Neurons, Nuclear Proteins, Phosphorylation, Point Mutation, Protein Binding, Protein Structure, Tertiary, RNA, Messenger, Transcription, Genetic, Transfection, Tumor Cells, Cultured, Two-Hybrid System Techniques, Xenopus, 12881483}, Month = {Aug}, Number = {16}, Pages = {9578-83}, Pii = {1133382100}, Title = {{Stimulation of {N}}euro{D} activity by huntingtin and huntingtin-associated proteins {HAP}1 and {MLK}2.}, Url = {http://dx.doi.org/10.1073/pnas.1133382100}, Volume = {100}, Year = {2003}} @article{Matus2001, Author = {A. Matus}, Journal = {Nat Neurosci}, Month = {Oct}, Number = {10}, Pages = {967-968}, Title = {{Moving molecules make synapses.}}, Volume = {4}, Year = {2001}} @article{Matus2000, Annote = {The central nervous system functions primarily to convert patterns of activity in sensory receptors into patterns of muscle activity that constitute appropriate behavior. At the anatomical level this requires two complementary processes: a set of genetically encoded rules for building the basic network of connections, and a mechanism for subsequently fine tuning these connections on the basis of experience. Identifying the locus and mechanism of these structural changes has long been among neurobiology's major objectives. Evidence has accumulated implicating a particular class of contacts, excitatory synapses made onto dendritic spines, as the sites where connective plasticity occurs. New developments in light microscopy allow changes in spine morphology to be directly visualized in living neurons and suggest that a common mechanism, based on dynamic actin filaments, is involved in both the formation of dendritic spines during development and their structural plasticity at mature synapses.}, Author = {A. Matus}, Journal = {Science}, Keywords = {review}, Month = {Oct}, Number = {5492}, Pages = {754-758}, Title = {{Actin-based plasticity in dendritic spines.}}, Volume = {290}, Year = {2000}} @article{McGee2001, Annote = {Membrane-associated guanylate kinases (MAGUKs), such as PSD-95, are modular scaffolds that organize signaling complexes at synapses and other cell junctions. MAGUKs contain PDZ domains, which recruit signaling proteins, as well as a Src homology 3 (SH3) and a guanylate kinase-like (GK) domain, implicated in scaffold oligomerization. The crystal structure of the SH3-GK module from PSD-95 reveals that these domains form an integrated unit: the SH3 fold comprises noncontiguous sequence elements divided by a hinge region and the GK domain. These elements compose two subdomains that can assemble in either an intra- or intermolecular fashion to complete the SH3 fold. We propose a model for MAGUK oligomerization in which complementary SH3 subdomains associate by 3D domain swapping. This model provides a possible mechanism for ligand regulation of oligomerization.}, Author = {A. W. McGee and S. R. Dakoji and O. Olsen and D. S. Bredt and W. A. Lim and K. E. Prehoda}, Journal = {Mol Cell}, Month = {Dec}, Number = {6}, Pages = {1291-301}, Title = {{Structure of the SH3-guanylate kinase module from PSD-95 suggests a mechanism for regulated assembly of MAGUK scaffolding proteins.}}, Volume = {8}, Year = {2001}} @article{Migaud1998, Annote = {Specific patterns of neuronal firing induce changes in synaptic strength that may contribute to learning and memory. If the postsynaptic NMDA (N-methyl-D-aspartate) receptors are blocked, long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission and the learning of spatial information are prevented. The NMDA receptor can bind a protein known as postsynaptic density-95 (PSD-95), which may regulate the localization of and/or signalling by the receptor. In mutant mice lacking PSD-95, the frequency function of NMDA-dependent LTP and LTD is shifted to produce strikingly enhanced LTP at different frequencies of synaptic stimulation. In keeping with neural-network models that incorporate bidirectional learning rules, this frequency shift is accompanied by severely impaired spatial learning. Synaptic NMDA-receptor currents, subunit expression, localization and synaptic morphology are all unaffected in the mutant mice. PSD-95 thus appears to be important in coupling the NMDA receptor to pathways that control bidirectional synaptic plasticity and learning.}, Author = {M. Migaud and P. Charlesworth and M. Dempster and L. C. Webster and A. M. Watabe and M. Makhinson and Y. He and M. F. Ramsay and R. G. Morris and J. H. Morrison and T. J. O'Dell and S. G. Grant}, Journal = {Nature}, Month = {Dec}, Number = {6710}, Pages = {433-439}, Title = {{Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein.}}, Volume = {396}, Year = {1998}} @article{Morabito2004, Annote = {PSD-95 (postsynaptic density 95) is a postsynaptic scaffolding protein that links NMDA receptors to the cytoskeleton and signaling molecules. The N-terminal domain of PSD-95 is involved in the synaptic targeting and clustering of PSD-95 and in the clustering of NMDA receptors at synapses. The N-terminal domain of PSD-95 contains three consensus phosphorylation sites for cyclin-dependent kinase 5 (cdk5), a proline-directed serine-threonine kinase essential for brain development and implicated in synaptic plasticity, dopamine signaling, cocaine addiction, and neurodegenerative disorders. We report that PSD-95 is phosphorylated in the N-terminal domain by cdk5 in vitro and in vivo, and that this phosphorylation is not detectable in brain lysates of cdk5-/- mice. N-terminal phosphorylated PSD-95 is found in PSD fractions together with cdk5 and its activator, p35, suggesting a role for phosphorylated PSD-95 at synapses. In heterologous cells, coexpression of active cdk5 reduces the ability of PSD-95 to multimerize and to cluster neuronal ion channels, two functions attributed to the N-terminal domain of PSD-95. Consistent with these observations, the lack of cdk5 activity in cultured neurons results in larger clusters of PSD-95. In cdk5-/- cortical neurons, more prominent PSD-95 immunostained clusters are observed than in wild-type neurons. In hippocampal neurons, the expression of DNcdk5 (inactive form of cdk5) or of the triple alanine mutant (T19A, S25A, S35A) full-length PSD-95 results in increased PSD-95 cluster size. These results identify cdk5-dependent phosphorylation of the N-terminal domain of PSD-95 as a novel mechanism for regulating the clustering of PSD-95. Moreover, these observations support the possibility that cdk5-dependent phosphorylation of PSD-95 dynamically regulates the clustering of PSD-95/NMDA receptors at synapses, thus providing a possible mechanism for rapid changes in density and/or number of receptor at synapses.}, Author = {M. A. Morabito and M. Sheng and L. H. Tsai}, Journal = {J Neurosci}, Month = {Jan}, Number = {4}, Pages = {865-76}, Title = {{Cyclin-dependent kinase 5 phosphorylates the N-terminal domain of the postsynaptic density protein PSD-95 in neurons.}}, Volume = {24}, Year = {2004}} @article{Naisbitt1999, Annote = {NMDA receptors are linked to intracellular cytoskeletal and signaling molecules via the PSD-95 protein complex. We report a novel family of postsynaptic density (PSD) proteins, termed Shank, that binds via its PDZ domain to the C terminus of PSD-95-associated protein GKAP. A ternary complex of Shank/GKAP/PSD-95 assembles in heterologous cells and can be coimmunoprecipitated from rat brain. Synaptic localization of Shank in neurons is inhibited by a GKAP splice variant that lacks the Shank-binding C terminus. In addition to its PDZ domain, Shank contains a proline-rich region that binds to cortactin and a SAM domain that mediates multimerization. Shank may function as a scaffold protein in the PSD, potentially cross-linking NMDA receptor/PSD-95 complexes and coupling them to regulators of the actin cytoskeleton.}, Author = {S. Naisbitt and E. Kim and J. C. Tu and B. Xiao and C. Sala and J. Valtschanoff and R. J. Weinberg and P. F. Worley and M. Sheng}, Journal = {Neuron}, Month = {Jul}, Number = {3}, Pages = {569-82}, Title = {{Shank, a novel family of postsynaptic density proteins that binds to the NMDA receptor/PSD-95/GKAP complex and cortactin.}}, Volume = {23}, Year = {1999}} @article{Nimnual2002, Annote = {Son of sevenless (SOS) is a guanine nucleotide exchange factor that activates Ras in response to growth factor stimulation. SOS also appears to serve as a guanine nucleotide exchanger for Rac and, thus, may be involved in cytoskeleton reorganization. Nimnual and Bar-Sagi discuss how these two activities of SOS can be regulated and how SOS may be recruited to different cellular locations through interactions with the adaptor proteins Grb2 and E3b1.}, Author = {A. Nimnual and D. Bar-Sagi}, Journal = {Sci STKE}, Month = {Aug}, Number = {145}, Pages = {PE36}, Title = {{The two hats of SOS.}}, Volume = {2002}, Year = {2002}} @article{Nimnual1998, Annote = {The Son of Sevenless (Sos) proteins control receptor-mediated activation of Ras by catalyzing the exchange of guanosine diphosphate for guanosine triphosphate on Ras. The NH2-terminal region of Sos contains a Dbl homology (DH) domain in tandem with a pleckstrin homology (PH) domain. In COS-1 cells, the DH domain of Sos stimulated guanine nucleotide exchange on Rac but not Cdc42 in vitro and in vivo. The tandem DH-PH domain of Sos (DH-PH-Sos) was defective in Rac activation but regained Rac stimulating activity when it was coexpressed with activated Ras. Ras-mediated activation of DH-PH-Sos did not require activation of mitogen-activated protein kinase but it was dependent on activation of phosphoinositide 3-kinase. These results reveal a potential mechanism for coupling of Ras and Rac signaling pathways.}, Author = {A. S. Nimnual and B. A. Yatsula and D. Bar-Sagi}, Journal = {Science}, Month = {Jan}, Number = {5350}, Pages = {560-563}, Title = {{Coupling of Ras and Rac guanosine triphosphatases through the Ras exchanger Sos.}}, Volume = {279}, Year = {1998}} @article{Oh2004, Annote = {SynGAP is a neuron-specific Ras GTPase-activating protein found in high concentration in the postsynaptic density fraction from mammalian forebrain. Proteins in the postsynaptic density, including synGAP, are part of a signaling complex attached to the cytoplasmic tail of the N-methyl-D-aspartate-type glutamate receptor. SynGAP can be phosphorylated by a second prominent component of the complex, Ca(2+)/calmodulin-dependent protein kinase II. Here we show that phosphorylation of synGAP by Ca(2+)/calmodulin-dependent protein kinase II increases its Ras GTPase-activating activity by 70-95\%. We identify four major sites of phosphorylation, serine-1123, serine-1058, serine -750/751/756, and serine-764/765. These sites together with other minor phosphorylation sites in the carboxyl tail of synGAP control stimulation of GTPase-activating activity. When three of these sites and four other serines in the carboxyl tail are mutated, stimulation of GAP activity after phosphorylation is reduced to 21 5 \% compared to 70-95\% for the wild type protein. We used phosphosite-specific antibodies to show that, as predicted, phosphorylation of serine-765 and serine-1123 is increased in cultured cortical neurons after exposure of the neurons to the agonist N-methyl-D-aspartate.}, Author = {J. S. Oh and P. Manzerra and M. B. Kennedy}, Journal = {J Biol Chem}, Month = {Feb}, Title = {{Regulation of the neuron-specific Ras GTPase activating protein, synGAP, by Ca2+/calmodulin-dependent protein kinase II.}}, Year = {2004}} @article{Opazo2003, Annote = {Inhibitors of both phosphatidylinositol-3-kinase (PI3-kinase) and MAPK/ERK (mitogen-activate protein kinase/extracellular signal-related kinase) activation inhibit NMDA receptor-dependent long-term potentiation (LTP). PI3-kinase inhibitors also block activation of ERK by NMDA receptor stimulation, suggesting that PI3-kinase inhibitors block LTP because PI3-kinase is an essential upstream regulator of ERK activation. To examine this hypothesis, we investigated the effects of PI3-kinase inhibitors on ERK activation and LTP induction in the CA1 region of mouse hippocampal slices. Consistent with the notion that ERK activation by NMDA receptor stimulation is PI3-kinase dependent, the PI3-kinase inhibitor wortmannin partially inhibited ERK2 activation induced by bath application of NMDA and strongly suppressed ERK2 activation by high-frequency synaptic stimulation. PI3-kinase and MEK (MAP kinase kinase) inhibitors had very different effects on LTP, however. Both types of inhibitors suppressed LTP induced by theta-frequency trains of synaptic stimulation, but only PI3-kinase inhibitors suppressed the induction of LTP by high-frequency stimulation or low-frequency stimulation paired with postsynaptic depolarization. Concentrations of PI3-kinase inhibitors that inhibited LTP when present during high-frequency stimulation had no effect on potentiated synapses when applied after high-frequency stimulation, suggesting that PI3-kinase is specifically involved in the induction of LTP. Finally, we found that LTP induced by theta-frequency stimulation was MEK inhibitor insensitive but still PI3-kinase dependent in hippocampal slices from PSD-95 (postsynaptic density-95) mutant mice. Together, our results indicate that the role of PI3-kinase in LTP is not limited to its role as an upstream regulator of MAPK signaling but also includes signaling through ERK-independent pathways that regulate LTP induction.}, Author = {P. Opazo and A. M. Watabe and S. G. Grant and T. J. O'Dell}, Journal = {J Neurosci}, Month = {May}, Number = {9}, Pages = {3679-88}, Title = {{Phosphatidylinositol 3-kinase regulates the induction of long-term potentiation through extracellular signal-related kinase-independent mechanisms.}}, Volume = {23}, Year = {2003}} @article{Ostroff2002, Annote = {The presence of polyribosomes in dendritic spines suggests a potential involvement of local protein synthesis in the modification of synapses. Dendritic spine and synapse ultrastructure were compared after low-frequency control or tetanic stimulation in hippocampal slices from postnatal day (P)15 rats. The percentage of spines containing polyribosomes increased from 12\% +/- 4\% after control stimulation to 39\% +/- 4\% after tetanic stimulation, with a commensurate loss of polyribosomes from dendritic shafts at 2 hr posttetanus. Postsynaptic densities on spines containing polyribosomes were larger after tetanic stimulation. Local protein synthesis might therefore serve to stabilize stimulation-induced growth of the postsynaptic density. Furthermore, coincident polyribosomes and synapse enlargement might indicate spines that are expressing long-term potentiation induced by tetanic stimulation.}, Author = {L. E. Ostroff and J. C. Fiala and B. Allwardt and K. M. Harris}, Journal = {Neuron}, Keywords = {Kristen Harris}, Month = {Aug}, Number = {3}, Pages = {535-45}, Title = {{Polyribosomes redistribute from dendritic shafts into spines with enlarged synapses during LTP in developing rat hippocampal slices.}}, Volume = {35}, Year = {2002}} @article{Ouyang1997, Annote = {Autophosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII) at threonine-286 produces Ca2+-independent kinase activity and has been proposed to be involved in induction of long-term potentiation by tetanic stimulation in the hippocampus. We have used an immunocytochemical method to visualize and quantify the pattern of autophosphorylation of CaMKII in hippocampal slices after tetanization of the Schaffer collateral pathway. Thirty minutes after tetanic stimulation, autophosphorylated CaM kinase II (P-CaMKII) is significantly increased in area CA1 both in apical dendrites and in pyramidal cell somas. In apical dendrites, this increase is accompanied by an equally significant increase in staining for nonphosphorylated CaM kinase II. Thus, the increase in P-CaMKII appears to be secondary to an increase in the total amount of CaMKII. In neuronal somas, however, the increase in P-CaMKII is not accompanied by an increase in the total amount of CaMKII. We suggest that tetanic stimulation of the Schaffer collateral pathway may induce new synthesis of CaMKII molecules in the apical dendrites, which contain mRNA encoding its alpha-subunit. In neuronal somas, however, tetanic stimulation appears to result in long-lasting increases in P-CaMKII independent of an increase in the total amount of CaMKII. Our findings are consistent with a role for autophosphorylation of CaMKII in the induction and/or maintenance of long-term potentiation, but they indicate that the effects of tetanus on the kinase and its activity are not confined to synapses and may involve induction of new synthesis of kinase in dendrites as well as increases in the level of autophosphorylated kinase.}, Author = {Y. Ouyang and D. Kantor and K. M. Harris and E. M. Schuman and M. B. Kennedy}, Journal = {J Neurosci}, Month = {Jul}, Number = {14}, Pages = {5416-27}, Title = {{Visualization of the distribution of autophosphorylated calcium/calmodulin-dependent protein kinase II after tetanic stimulation in the CA1 area of the hippocampus.}}, Volume = {17}, Year = {1997}} @article{Ouyang1999, Annote = {mRNA for the alpha-subunit of CaMKII is abundant in dendrites of neurons in the forebrain (Steward, 1997). Here we show that tetanic stimulation of the Schaffer collateral pathway causes an increase in the concentration of alpha-CaMKII in the dendrites of postsynaptic neurons. The increase is blocked by anisomycin and is detected by both quantitative immunoblot and semiquantitative immunocytochemistry. The increase in dendritic alpha-CaMKII can be measured 100-200 micrometer away from the neuronal cell bodies as early as 5 min after a tetanus. Transport mechanisms for macromolecules from neuronal cell bodies are not fast enough to account for this rapid increase in distal portions of the dendrites. Therefore, we conclude that dendritic protein synthesis must produce a portion of the newly accumulated CaMKII. The increase in concentration of dendritic CaMKII after tetanus, together with the previously demonstrated increase in autophosphorylated CaMKII (Ouyang et al., 1997), will produce a prolonged increase in steady-state kinase activity in the dendrites, potentially influencing mechanisms of synaptic plasticity that are controlled through phosphorylation by CaMKII.}, Author = {Y. Ouyang and A. Rosenstein and G. Kreiman and E. M. Schuman and M. B. Kennedy}, Journal = {J Neurosci}, Month = {Sep}, Number = {18}, Pages = {7823-33}, Title = {{Tetanic stimulation leads to increased accumulation of Ca(2+)/calmodulin-dependent protein kinase II via dendritic protein synthesis in hippocampal neurons.}}, Volume = {19}, Year = {1999}} @article{Pak2003, Annote = {Synaptic plasticity involves the reorganization of synapses at the protein and the morphological levels. Here, we report activity-dependent remodeling of synapses by serum-inducible kinase (SNK). SNK was induced in hippocampal neurons by synaptic activity and was targeted to dendritic spines. SNK bound to and phosphorylated spine-associated Rap guanosine triphosphatase activating protein (SPAR), a postsynaptic actin regulatory protein, leading to degradation of SPAR. Induction of SNK in hippocampal neurons eliminated SPAR protein, depleted postsynaptic density-95 and Bassoon clusters, and caused loss of mature dendritic spines. These results implicate SNK as a mediator of activity-dependent change in the molecular composition and morphology of synapses.}, Author = {D. T. Pak and M. Sheng}, Journal = {Science}, Month = {Nov}, Number = {5649}, Pages = {1368-73}, Title = {{Targeted protein degradation and synapse remodeling by an inducible protein kinase.}}, Volume = {302}, Year = {2003}} @article{Pak2001, Annote = {The PSD-95/SAP90 family of scaffold proteins organizes the postsynaptic density (PSD) and regulates NMDA receptor signaling at excitatory synapses. We report that SPAR, a Rap-specific GTPase-activating protein (RapGAP), interacts with the guanylate kinase-like domain of PSD-95 and forms a complex with PSD-95 and NMDA receptors in brain. In heterologous cells, SPAR reorganizes the actin cytoskeleton and recruits PSD-95 to F-actin. In hippocampal neurons, SPAR localizes to dendritic spines and causes enlargement of spine heads, many of which adopt an irregular appearance with putative multiple synapses. Dominant negative SPAR constructs cause narrowing and elongation of spines. The effects of SPAR on spine morphology depend on the RapGAP and actin-interacting domains, implicating Rap signaling in the regulation of postsynaptic structure.}, Author = {D. T. Pak and S. Yang and S. Rudolph-Correia and E. Kim and M. Sheng}, Journal = {Neuron}, Month = {Aug}, Number = {2}, Pages = {289-303}, Title = {{Regulation of dendritic spine morphology by SPAR, a PSD-95-associated RapGAP.}}, Volume = {31}, Year = {2001}} @article{Passafaro2003, Annote = {Synaptic transmission from excitatory nerve cells in the mammalian brain is largely mediated by AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-type glutamate receptors located at the surface of dendritic spines. The abundance of postsynaptic AMPA receptors correlates with the size of the synapse and the dimensions of the dendritic spine head. Moreover, long-term potentiation is associated with the formation of dendritic spines as well as synaptic delivery of AMPA receptors. The molecular mechanisms that coordinate AMPA receptor delivery and spine morphogenesis are unknown. Here we show that overexpression of the glutamate receptor 2 (GluR2) subunit of AMPA receptors increases spine size and density in hippocampal neurons, and more remarkably, induces spine formation in GABA-releasing interneurons that normally lack spines. The extracellular N-terminal domain (NTD) of GluR2 is responsible for this effect, and heterologous fusion proteins of the NTD of GluR2 inhibit spine morphogenesis. We propose that the NTD of GluR2 functions at the cell surface as part of a receptor-ligand interaction that is important for spine growth and/or stability.}, Author = {M. Passafaro and T. Nakagawa and C. Sala and M. Sheng}, Journal = {Nature}, Month = {Aug}, Number = {6949}, Pages = {677-81}, Title = {{Induction of dendritic spines by an extracellular domain of AMPA receptor subunit GluR2.}}, Volume = {424}, Year = {2003}} @article{Pei2001, Annote = {Cerebral ischemia results in activation of the mitogen-activated protein kinase pathway and increased tyrosine phosphorylation of proteins associated with postsynaptic densities (PSDs). The authors investigated the possible relation between these events by determining the effect of ischemia on tyrosine phosphorylation of the brain-specific, PSD-enriched, Ras-GTPase activating protein, SynGAP. Transient (15 minutes) global ischemia was produced in rats by 4-vessel occlusion and PSDs prepared from forebrains immediately after ischemia or at 20 minutes, 1 hour, or 24 hours of reperfusion. Tyrosine phosphorylation of SynGAP was elevated relative to sham-operated controls by 20 minutes of reperfusion and remained elevated for at least 24 hours. Tyrosine phosphorylation of SynGAP also increased in CA1 and CA3/DG subfields of the hippocampus. Enhanced tyrosine phosphorylation of SynGAP was not accompanied by a change in PSD RasGAP activity. SynGAP bound to the SH2 domains of Src and Fyn in a tyrosine phosphorylation-dependent fashion, and this interaction increased after ischemia. SynGAP binds to the PDZ domains of PSD-95/SAP90 and coimmunoprecipitated with PSD-95. The coimmunoprecipitation of SynGAP with PSD-95 decreased after ischemia. The results indicate that changes in the properties and interactions of SynGAP may be involved in the neuropathology of ischemia.}, Author = {L. Pei and R. L. Teves and M. C. Wallace and J. W. Gurd}, Journal = {J Cereb Blood Flow Metab}, Month = {Aug}, Number = {8}, Pages = {955-63}, Title = {{Transient cerebral ischemia increases tyrosine phosphorylation of the synaptic RAS-GTPase activating protein, SynGAP.}}, Volume = {21}, Year = {2001}} @article{Penzes2003, Annote = {The morphogenesis of dendritic spines, the major sites of excitatory synaptic transmission in the brain, is important in synaptic development and plasticity. We have identified an ephrinB-EphB receptor trans-synaptic signaling pathway which regulates the morphogenesis and maturation of dendritic spines in hippocampal neurons. Activation of the EphB receptor induces translocation of the Rho-GEF kalirin to synapses and activation of Rac1 and its effector PAK. Overexpression of dominant-negative EphB receptor, catalytically inactive kalirin, or dominant-negative Rac1, or inhibition of PAK eliminates ephrin-induced spine development. This novel signal transduction pathway may be critical for the regulation of the actin cytoskeleton controlling spine morphogenesis during development and plasticity.}, Author = {P. Penzes and A. Beeser and J. Chernoff and M. R. Schiller and B. A. Eipper and R. E. Mains and R. L. Huganir}, Journal = {Neuron}, Month = {Jan}, Number = {2}, Pages = {263-74}, Title = {{Rapid induction of dendritic spine morphogenesis by trans-synaptic ephrinB-EphB receptor activation of the Rho-GEF kalirin.}}, Volume = {37}, Year = {2003}} @article{Poncer2002, Annote = {Some forms of activity-dependent synaptic potentiation require the activation of postsynaptic Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). Activation of CaMKII has been shown to phosphorylate the glutamate receptor 1 subunit of the AMPA receptor (AMPAR), thereby affecting some of the properties of the receptor. Here, a recombinant, constitutively active form of alphaCaMKII tagged with the fluorescent marker green fluorescent protein (GFP) [alphaCaMKII(1-290)-enhanced GFP (EGFP)] was expressed in CA1 pyramidal neurons from hippocampal slices. The changes in glutamatergic transmission onto these cells were analyzed. AMPA but not NMDA receptor-mediated EPSCs were specifically potentiated in infected compared with nearby noninfected neurons. This potentiation was associated with a reduction in the proportion of synapses devoid of AMPARs. In addition, expression of alphaCaMKII(1-290)-EGFP increased the quantal size of AMPAR-mediated responses. This effect reflected, at least in part, an increased unitary conductance of the channels underlying the EPSCs. These results reveal that several key features of long-term potentiation of hippocampal glutamatergic synapses are reproduced by the sole activity of alphaCaMKII.}, Author = {J. C. Poncer and J. A. Esteban and R. Malinow}, Journal = {J Neurosci}, Month = {Jun}, Number = {11}, Pages = {4406-11}, Title = {{Multiple mechanisms for the potentiation of AMPA receptor-mediated transmission by alpha-Ca2+/calmodulin-dependent protein kinase II.}}, Volume = {22}, Year = {2002}} @article{Cajal1891, Author = {Ramon y Cajal, S}, Journal = {Revista de Ciencias Medicas de Barcelona}, Number = {22}, Pages = {23}, Title = {{Significaci\'on fisiol\'ogica de las expanciones protopl\'asmicas y nerviosas de la sustancia gris}}, Year = {1891}} @article{Cajal1888, Author = {Ramon y Cajal, S}, Journal = {Rev. Trim. Histol. Norm. Pat}, Number = {1}, Pages = {1-10}, Title = {{Estructura de los centros nerviosos de las aves}}, Year = {1888}} @article{Cajal1899, Author = {Ramon y Cajal, S}, Journal = {(Madrid:Moya)}, Title = {{La Textura del Sistema Nervioso del Hombre y los Vertebrados}}} @article{Rao1997, Annote = {We describe here a novel effect of activity on the subcellular distribution of NMDA receptors in hippocampal neurons in culture. In spontaneously active neurons, NMDA receptors were clustered at a few synaptic and nonsynaptic sites. Chronic blockade of NMDA receptor activity induced a 380\% increase in the number of NMDA receptor clusters and a shift to a more synaptic distribution. This effect was reversible. The distributions of the presynaptic marker synaptophysin, the AMPA-type glutamate receptor subunit GluR1, and the putative NMDA receptor clustering protein PSD-95 were not affected by blockade. Regulation of the synaptic localization of NMDA receptors by activity may define a novel mechanism by which input controls a neuron's ability to modify its synapses.}, Author = {A. Rao and A. M. Craig}, Journal = {Neuron}, Keywords = {AM Craig}, Month = {Oct}, Number = {4}, Pages = {801-12}, Title = {{Activity regulates the synaptic localization of the NMDA receptor in hippocampal neurons.}}, Volume = {19}, Year = {1997}} @article{Rao1998, Annote = {To determine their roles in the assembly of glutamatergic postsynaptic sites, we studied the distributions of NMDA- and AMPA-type glutamate receptors; the NMDA receptor-interacting proteins alpha-actinin-2, PSD-95, and chapsyn; and the PSD-95-associated protein GKAP during the development of hippocampal neurons in culture. NMDA receptors first formed nonsynaptic proximal dendrite shaft clusters within 2-5 d. AMPA receptors were diffuse at this stage and began to cluster on spines at 9-10 d. NMDA receptor clusters remained partially nonsynaptic and mainly distinct from AMPA receptor clusters until after 3 weeks in culture, when the two began to colocalize at spiny synaptic sites. Thus, the localization of NMDA and AMPA receptors must be regulated by different mechanisms. alpha-Actinin-2 colocalized with the NMDA receptor only at spiny synaptic clusters, but not at shaft nonsynaptic or synaptic clusters, suggesting a modulatory role in the anchoring of NMDA receptor at spines. PSD-95, chapsyn, and GKAP were present at some, but not all, nonsynaptic NMDA receptor clusters during the first 2 weeks, indicating that none is essential for NMDA receptor cluster formation. When NMDA receptor clusters became synaptic, PSD-95 and GKAP were always present, consistent with an essential function in synaptic localization of NMDA receptors. Furthermore, PSD-95 and GKAP clustered opposite presynaptic terminals several days before either NMDA or AMPA receptors clustered at these presumptive postsynaptic sites. These results suggest that synapse development proceeds by formation of a postsynaptic scaffold containing PSD-95 and GKAP in concert with presynaptic vesicle clustering, followed by regulated attachment of glutamate receptor subtypes to this scaffold.}, Author = {A. Rao and E. Kim and M. Sheng and A. M. Craig}, Journal = {J Neurosci}, Month = {Feb}, Number = {4}, Pages = {1217-29}, Title = {{Heterogeneity in the molecular composition of excitatory postsynaptic sites during development of hippocampal neurons in culture.}}, Volume = {18}, Year = {1998}} @article{Ridley1992, Annote = {The function of rac, a ras-related GTP-binding protein, was investigated in fibroblasts by microinjection. In confluent serum-starved Swiss 3T3 cells, rac1 rapidly stimulated actin filament accumulation at the plasma membrane, forming membrane ruffles. Several growth factors and activated H-ras also induced membrane ruffling, and this response was prevented by a dominant inhibitory mutant rac protein, N17rac1. This suggests that endogenous rac proteins are required for growth factor-induced membrane ruffling. In addition to membrane ruffling, a later response to both rac1 microinjection and some growth factors was the formation of actin stress fibers, a process requiring endogenous rho proteins. Using N17rac1 we have shown that these growth factors act through rac to stimulate this rho-dependent response. We propose that rac and rho are essential components of signal transduction pathways linking growth factors to the organization of polymerized actin.}, Author = {A. J. Ridley and H. F. Paterson and C. L. Johnston and D. Diekmann and A. Hall}, Journal = {Cell}, Month = {Aug}, Number = {3}, Pages = {401-10}, Title = {{The small GTP-binding protein rac regulates growth factor-induced membrane ruffling.}}, Volume = {70}, Year = {1992}} @article{Roche2001, Annote = {Although synaptic AMPA receptors have been shown to rapidly internalize, synaptic NMDA receptors are reported to be static. It is not certain whether NMDA receptor stability at synaptic sites is an inherent property of the receptor, or is due to stabilization by scaffolding proteins. In this study, we demonstrate that NMDA receptors are internalized in both heterologous cells and neurons, and we define an internalization motif, YEKL, on the distal C-terminus of NR2B. In addition, we show that the synaptic protein PSD-95 inhibits NR2B-mediated internalization, and that deletion of the PDZ-binding domain of NR2B increases internalization in neurons. This suggests an involvement for PSD-95 in NMDA receptor regulation and an explanation for NMDA receptor stability at synaptic sites.}, Author = {K. W. Roche and S. Standley and J. McCallum and C. Dune Ly and M. D. Ehlers and R. J. Wenthold}, Journal = {Nat Neurosci}, Keywords = {Ehlers}, Month = {Aug}, Number = {8}, Pages = {794-802}, Title = {{Molecular determinants of NMDA receptor internalization.}}, Volume = {4}, Year = {2001}} @article{Rodriguez-Viciana1994, Annote = {Ras (p21ras) interacts directly with the catalytic subunit of phosphatidylinositol-3-OH kinase in a GTP-dependent manner through the Ras effector site. In vivo, dominant negative Ras mutant N17 inhibits growth factor induced production of 3' phosphorylated phosphoinositides in PC12 cells, and transfection of Ras, but not Raf, into COS cells results in a large elevation in the level of these lipids. Therefore Ras can probably regulate phosphatidylinositol-3-OH kinase, providing a point of divergence in signalling pathways downstream of Ras.}, Author = {P. Rodriguez-Viciana and P. H. Warne and R. Dhand and B. Vanhaesebroeck and I. Gout and M. J. Fry and M. D. Waterfield and J. Downward}, Journal = {Nature}, Month = {Aug}, Number = {6490}, Pages = {527-32}, Title = {{Phosphatidylinositol-3-OH kinase as a direct target of Ras.}}, Volume = {370}, Year = {1994}} @article{Rodriguez-Viciana1997, Author = {P. Rodriguez-Viciana and P. H. Warne and A. Khwaja and B. M. Marte and D. Pappin and P. Das and M. D. Waterfield and A. Ridley and J. Downward}, Journal = {Cell}, Month = {May}, Number = {3}, Pages = {457-67}, Title = {{Role of phosphoinositide 3-OH kinase in cell transformation and control of the actin cytoskeleton by Ras.}}, Volume = {89}, Year = {1997}} @article{Sala2003, Annote = {The postsynaptic density (PSD) proteins Shank and Homer cooperate to induce the maturation and enlargement of dendritic spines (Sala et al., 2001). Homer1a is an activity-inducible short-splice variant of Homer that lacks dimerization capacity. Here, we show that Homer1a reduces the density and size of dendritic spines in cultured hippocampal neurons in correlation with an inhibition of Shank targeting to synapses. Expression of Homer1a also decreases the size of PSD-95 clusters, the number of NMDA receptor clusters, and the level of surface AMPA receptors, implying a negative effect on the growth of synapses. In parallel with the morphological effects on synapses, Homer1a-expressing neurons show diminished AMPA and NMDA receptor postsynaptic currents. All of these outcomes required the integrity of the Ena/VASP Homology 1 domain of Homer1a that mediates binding to the PPXXF motif in Shank and other binding partners. Overexpression of the C-terminal region of Shank containing the Homer binding site causes effects similar to those of Homer1a. These data indicate that an association between Shank and the constitutively expressed long-splice variants of Homer (e.g., Homer1b/c) is important for maintaining dendritic-spine structure and synaptic function. Because Homer1a expression is induced by synaptic activity, our results suggest that this splice variant of Homer operates in a negative feedback loop to regulate the structure and function of synapses in an activity-dependent manner.}, Author = {C. Sala and K. Futai and K. Yamamoto and P. F. Worley and Y. Hayashi and M. Sheng}, Journal = {J Neurosci}, Month = {Jul}, Number = {15}, Pages = {6327-37}, Title = {{Inhibition of dendritic spine morphogenesis and synaptic transmission by activity-inducible protein Homer1a.}}, Volume = {23}, Year = {2003}} @article{Sala2001, Annote = {The Shank family of proteins interacts with NMDA receptor and metabotropic glutamate receptor complexes in the postsynaptic density (PSD). Targeted to the PSD by a PDZ-dependent mechanism, Shank promotes the maturation of dendritic spines and the enlargement of spine heads via its ability to recruit Homer to postsynaptic sites. Shank and Homer cooperate to induce accumulation of IP3 receptors in dendritic spines and formation of putative multisynapse spines. In addition, postsynaptic expression of Shank enhances presynaptic function, as measured by increased minifrequency and FM4-64 uptake. These data suggest a central role for the Shank scaffold in the structural and functional organization of the dendritic spine and synaptic junction.}, Author = {C. Sala and V. Piech and N. R. Wilson and M. Passafaro and G. Liu and M. Sheng}, Journal = {Neuron}, Month = {Jul}, Number = {1}, Pages = {115-30}, Title = {{Regulation of dendritic spine morphology and synaptic function by Shank and Homer.}}, Volume = {31}, Year = {2001}} @article{Sala2000, Annote = {Developmental changes in the signaling properties of NMDA receptors have been proposed to underlie the loss of plasticity that accompanies brain maturation. Calcium influx through postsynaptic NMDA receptors can stimulate neuronal gene expression via signaling pathways such as the Ras-MAP kinase (MAPK) pathway and the transcription factor cAMP response element-binding protein (CREB). We analyzed MAPK (Erk1/2) and CREB activation in response to NMDA receptor stimulation during the development of hippocampal neurons in culture. At all stages of development NMDA stimulation induced a rapid phosphorylation of CREB on Ser-133 (phospho-CREB). However, the time course of decline in phospho-CREB changed dramatically with neuronal maturation. At 7 d in vitro (7 DIV) phospho-CREB remained elevated 2 hr after strong NMDA stimulation, whereas at 14 DIV phospho-CREB rose only transiently and fell back to below basal levels within 30 min. Moreover, at 14 DIV, but not at 7 DIV, NMDA receptor stimulation induced a dephosphorylation of CREB that previously had been phosphorylated by KCl depolarization or forskolin, suggesting an NMDA receptor-dependent activation of a CREB phosphatase. There was no developmental change in the time course of phospho-CREB induction that followed KCl depolarization or PKA activation, nor was there a developmental change in the time course of phospho-Erk1/2 induced by NMDA receptor activation. We suggest that, during neuronal maturation, NMDA receptor activation becomes linked specifically to protein phosphatases that act on Ser-133 of CREB. Such a developmentally regulated switch in the mode of NMDA receptor coupling to intracellular signaling pathways may contribute to the changes in neural plasticity observed during brain development.}, Author = {C. Sala and S. Rudolph-Correia and M. Sheng}, Journal = {J Neurosci}, Month = {May}, Number = {10}, Pages = {3529-36}, Title = {{Developmentally regulated NMDA receptor-dependent dephosphorylation of cAMP response element-binding protein (CREB) in hippocampal neurons.}}, Volume = {20}, Year = {2000}} @article{Scannevin2000, Annote = {Dynamic regulation of synaptic efficacy is one of the mechanisms thought to underlie learning and memory. Many of the observed changes in efficacy, such as long-term potentiation and long-term depression, result from the functional alteration of excitatory neurotransmission mediated by postsynaptic glutamate receptors. These changes may result from the modulation of the receptors themselves and from regulation of protein networks associated with glutamate receptors. Understanding the interactions in this synaptic complex will yield invaluable insight into the molecular basis of synaptic function. This review focuses on the molecular organization of excitatory synapses and the processes involved in the dynamic regulation of glutamate receptors.}, Author = {R. H. Scannevin and R. L. Huganir}, Journal = {Nat Rev Neurosci}, Month = {Nov}, Number = {2}, Pages = {133-41}, Title = {{Postsynaptic organization and regulation of excitatory synapses.}}, Volume = {1}, Year = {2000}} @article{Sheng2001b, Annote = {A specific set of molecules including glutamate receptors is targeted to the postsynaptic specialization of excitatory synapses in the brain, gathering in a structure known as the postsynaptic density (PSD). Synaptic targeting of glutamate receptors depends on interactions between the C-terminal tails of receptor subunits and specific PDZ domain-containing scaffold proteins in the PSD. These scaffold proteins assemble a specialized protein complex around each class of glutamate receptor that functions in signal transduction, cytoskeletal anchoring, and trafficking of the receptors. Among the glutamate receptor subtypes, the N-methyl-d-aspartate receptor is relatively stably integrated in the PSD, whereas the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor moves in and out of the postsynaptic membrane in highly dynamic fashion. The distinctive cell biological behaviors of N-methyl-d-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors can be explained by their differential interactions with cytoplasmic proteins.}, Author = {M. Sheng}, Journal = {Proc Natl Acad Sci U S A}, Keywords = {review}, Month = {Jun}, Number = {13}, Pages = {7058-61}, Title = {{Molecular organization of the postsynaptic specialization.}}, Volume = {98}, Year = {2001}} @article{Sheng2000, Annote = {Shank proteins make up a new family of scaffold proteins recently identified through their interaction with a variety of membrane and cytoplasmic proteins. Shank polypeptides contain multiple sites for protein-protein interaction, including ankyrin repeats, an SH3 domain, a PDZ domain, a long proline-rich region, and a SAM domain. Binding partners for most of these domains have been identified: for instance, the PDZ domain of Shank proteins interacts with GKAP (a postsynaptic-density protein) as well as several G-protein-coupled receptors. The specific localization of Shank proteins at postsynaptic sites of brain excitatory synapses suggests a role for this family of proteins in the organization of cytoskeletal/ signaling complexes at specialized cell junctions.}, Author = {M. Sheng and E. Kim}, Journal = {J Cell Sci}, Month = {Jun}, Pages = {1851-1856}, Title = {{The Shank family of scaffold proteins.}}, Volume = {113 ( Pt 11)}, Year = {2000}} @article{Sheng2001c, Author = {M. Sheng and S. H. Lee}, Journal = {Cell}, Keywords = {review}, Month = {Jun}, Number = {7}, Pages = {825-828}, Title = {{AMPA receptor trafficking and the control of synaptic transmission.}}, Volume = {105}, Year = {2001}} @article{Sheng2001, Annote = {PDZ domains are modular protein interaction domains that bind in a sequence-specific fashion to short C-terminal peptides or internal peptides that fold in a beta-finger. The diversity of PDZ binding specificities can be explained by variable amino acids lining the peptide-binding groove of the PDZ domain. Abundantly represented in Caenorhabditis elegans, Drosophila melanogaster, and mammalian genomes, PDZ domains are frequently found in multiple copies or are associated with other protein-binding motifs in multidomain scaffold proteins. PDZ-containing proteins are typically involved in the assembly of supramolecular complexes that perform localized signaling functions at particular subcellular locations. Organization around a PDZ-based scaffold allows the stable localization of interacting proteins and enhances the rate and fidelity of signal transduction within the complex. Some PDZ-containing proteins are more dynamically regulated in distribution and may also be involved in the trafficking of interacting proteins within the cell.}, Author = {M. Sheng and C. Sala}, Journal = {Annu Rev Neurosci}, Pages = {1-29}, Title = {{PDZ domains and the organization of supramolecular complexes.}}, Volume = {24}, Year = {2001}} @article{Shi2001, Annote = {AMPA-type glutamate receptors (AMPA-Rs) mediate a majority of excitatory synaptic transmission in the brain. In hippocampus, most AMPA-Rs are hetero-oligomers composed of GluR1/GluR2 or GluR2/GluR3 subunits. Here we show that these AMPA-R forms display different synaptic delivery mechanisms. GluR1/GluR2 receptors are added to synapses during plasticity; this requires interactions between GluR1 and group I PDZ domain proteins. In contrast, GluR2/GluR3 receptors replace existing synaptic receptors continuously; this occurs only at synapses that already have AMPA-Rs and requires interactions by GluR2 with NSF and group II PDZ domain proteins. The combination of regulated addition and continuous replacement of synaptic receptors can stabilize long-term changes in synaptic efficacy and may serve as a general model for how surface receptor number is established and maintained.}, Author = {S. Shi and Y. Hayashi and J. A. Esteban and R. Malinow}, Journal = {Cell}, Month = {May}, Number = {3}, Pages = {331-43}, Title = {{Subunit-specific rules governing AMPA receptor trafficking to synapses in hippocampal pyramidal neurons.}}, Volume = {105}, Year = {2001}} @article{Shi1999, Annote = {To monitor changes in alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor distribution in living neurons, the AMPA receptor subunit GluR1 was tagged with green fluorescent protein (GFP). This protein (GluR1-GFP) was functional and was transiently expressed in hippocampal CA1 neurons. In dendrites visualized with two-photon laser scanning microscopy or electron microscopy, most of the GluR1-GFP was intracellular, mimicking endogenous GluR1 distribution. Tetanic synaptic stimulation induced a rapid delivery of tagged receptors into dendritic spines as well as clusters in dendrites. These postsynaptic trafficking events required synaptic N-methyl-D-aspartate (NMDA) receptor activation and may contribute to the enhanced AMPA receptor-mediatedtransmission observed during long-term potentiation and activity-dependent synaptic maturation.}, Author = {S. H. Shi and Y. Hayashi and R. S. Petralia and S. H. Zaman and R. J. Wenthold and K. Svoboda and R. Malinow}, Journal = {Science}, Month = {Jun}, Number = {5421}, Pages = {1811-1816}, Title = {{Rapid spine delivery and redistribution of AMPA receptors after synaptic NMDA receptor activation.}}, Volume = {284}, Year = {1999}} @article{Silva1992, Annote = {As a first step in a program to use genetically altered mice in the study of memory mechanisms, mutant mice were produced that do not express the alpha-calcium-calmodulin-dependent kinase II (alpha-CaMKII). The alpha-CaMKII is highly enriched in postsynaptic densities of hippocampus and neocortex and may be involved in the regulation of long-term potentiation (LTP). Such mutant mice exhibited mostly normal behaviors and presented no obvious neuroanatomical defects. Whole cell recordings reveal that postsynaptic mechanisms, including N-methyl-D-aspartate (NMDA) receptor function, are intact. Despite normal postsynaptic mechanisms, these mice are deficient in their ability to produce LTP and are therefore a suitable model for studying the relation between LTP and learning processes.}, Author = {A. J. Silva and C. F. Stevens and S. Tonegawa and Y. Wang}, Journal = {Science}, Keywords = {CamKII}, Month = {Jul}, Number = {5067}, Pages = {201-206}, Title = {{Deficient hippocampal long-term potentiation in alpha-calcium-calmodulin kinase II mutant mice.}}, Volume = {257}, Year = {1992}} @article{Silva1992b, Author = {A. J. Silva and Y. Wang and R. Paylor and J. M. Wehner and C. F. Stevens and S. Tonegawa}, Journal = {Cold Spring Harb Symp Quant Biol}, Keywords = {review}, Pages = {527-39}, Title = {{Alpha calcium/calmodulin kinase II mutant mice: deficient long-term potentiation and impaired spatial learning.}}, Volume = {57}, Year = {1992}} @article{Sjostrom2002, Annote = {Plasticity at central synapses depends critically on the timing of presynaptic and postsynaptic action potentials. Key initial steps in synaptic plasticity involve the back-propagation of action potentials into the dendritic tree and calcium influx that depends nonlinearly on the action potential and synaptic input. These initial steps are now better understood. In addition, recent studies of processes as diverse as gene expression and channel inactivation suggest that responses to calcium transients depend not only their amplitude, but on their time course and on the location of their origin.}, Author = {P. J. Sjostrom and S. B. Nelson}, Journal = {Curr Opin Neurobiol}, Month = {Jun}, Number = {3}, Pages = {305-14}, Title = {{Spike timing, calcium signals and synaptic plasticity.}}, Volume = {12}, Year = {2002}} @article{Skinner1991, Annote = {The C-terminal catalytic domain (residues 704-1047) of the human ras GTPase-activating protein (GAP) has been engineered so as to incorporate the tripeptide, Glu-Glu-Phe, at its C terminus. This motif is recognized by the commercially available YL1/2 monoclonal antibody to alpha-tubulin and has previously been used for the immunoaffinity purification of HIV enzymes engineered to contain this epitope (Stammers, D. K., Tisdale, M., Court, S., Parmar, V., Bradley, C., and Ross, C. K. (1991) FEBS Lett. 283, 298-302). The engineered GAP catalytic domain (GAP-344) was obtained in high yield and purity from Escherichia coli extracts by means of a single affinity column of immobilized YL1/2, eluted under mild conditions with the dipeptide, Asp-Phe. The protein had similar activity to that previously described for full-length GAP, suggesting that the addition of the epitope did not grossly affect the activity. R903K and L902I mutants of GAP-344 were constructed, and the immunoaffinity purification procedure allowed their rapid characterization. The R903K mutant had less than 3\% the activity of the normal protein, whereas the L902I substitution had less than 0.5\% of normal activity, suggesting an important role for Leu-902 and Arg-903, residues absolutely conserved among GAP-related proteins. This work exemplifies the general utility of the C-terminal Glu-Glu-Phe motif for the rapid purification of proteins whose function is not altered by C-terminal modification.}, Author = {R. H. Skinner and S. Bradley and A. L. Brown and N. J. Johnson and S. Rhodes and D. K. Stammers and P. N. Lowe}, Journal = {J Biol Chem}, Month = {Aug}, Number = {22}, Pages = {14163-14166}, Title = {{Use of the Glu-Glu-Phe C-terminal epitope for rapid purification of the catalytic domain of normal and mutant ras GTPase-activating proteins.}}, Volume = {266}, Year = {1991}} @article{Song2003, Annote = {The interaction between translocated calcium/calmdulin-dependent protein kinase IIalpha (CaMK IIalpha) and SynGAP during brain ischemia was investigated by Western blotting and immunoprecipitation. Brain ischemia was induced by the four-vessel occlusion method on Sprague-Dawley rats. After 3 min global ischemia, both the binding of CaMK IIalpha to SynGAP and the serine phosphorylation of SynGAP all dramatically increased. Administrating KN-62 through cerebral ventricle (20 min before ischemia) not only remarkably decreased the binding of CaMK IIalpha to SynGAP but also attenuate the elevated serine phosphorylation of SynGAP following 20 min ischemia in hippocampus. These results suggest that CaMK IIalpha is responsible for the serine phosphorylation of SynGAP and a consequent phosphorylation and inhibition of SynGAP may result in activation of mitogen-activated protein kinase pathway which could serve a protective function in brain ischemia.}, Author = {B. Song and F. Meng and X. Yan and J. Guo and G. Zhang}, Journal = {Neurosci Lett}, Month = {Oct}, Number = {3}, Pages = {183-186}, Title = {{Cerebral ischemia immediately increases serine phosphorylation of the synaptic RAS-GTPase activating protein SynGAP by calcium/calmodulin-dependent protein kinase II alpha in hippocampus of rats.}}, Volume = {349}, Year = {2003}} @article{Song2004, Annote = {Recent studies have indicated that cerebral ischemia induces rapid serine phosphorylation of synaptic RAS-GTPase activating protein (SynGAP) by calcium/Camodulin-dependent protein kinase II (CaMKII) in rat hippocampus. To further illustrate the mechanisms underlying these processes, we examined the effects of transient (15 min) brain ischemia followed by reperfusion (0, 30 min, 6 h, 1, 3 days) on serine phosphorylation of SynGAP and interactions involving SynGAP, postsynaptic density protein 95 (PSD95) and CaMKII in rat hippocampus. Transient brain ischemia was induced by the method of four-vessel occlusion in Sprague-Dawley rats. Serine phosphorylation of SynGAP increased immediately after brain ischemia and peaked at 30-min reperfusion, and the increase was maintained for 3 days. The association among SynGAP, PSD95 and CaMKII had a similar trend as serine phosphorylation of SynGAP. Intracrebroventricular infusion of PSD95 antisense oligodeoxynucleotide not only markedly decreased the protein levels of PSD95 but also attenuated the elevated serine phosphorylation of SynGAP and the associations among SynGAP, PSD95 and CaMKII induced by 30-min reperfusion following 15-min brain ischemia. The results suggest that the serine phosphorylation of SynGAP catalyzed by CaMKII is immediately increased and that PSD95 is critical for promoting SynGAP serine phosphorylation after transient brain ischemia.}, Author = {B. Song and X. B. Yan and G. Y. Zhang}, Journal = {Brain Res}, Month = {Apr}, Number = {1-2}, Pages = {44-50}, Title = {{PSD-95 promotes CaMKII-catalyzed serine phosphorylation of the synaptic RAS-GTPase activating protein SynGAP after transient brain ischemia in rat hippocampus.}}, Volume = {1005}, Year = {2004}} @article{Sorra1998, Annote = {Several studies propose that long-term enhancement of synaptic transmission between neurons results from the enlargement, perforation, and splitting of synapses and dendritic spines. Unbiased analyses through serial electron microscopy were used to assess the morphological basis for synapse spilitting in hippocampal area CA1. Few perforated synapses and almost no split (i.e., branched) spines occurred at postnatal day 15, an age of high synaptogenesis; thus, synapse splitting is unlikely to be important during development. The synapse splitting hypothesis predicts an intermediate stage of branched spines with both heads sharing the same presynaptic bouton. Ninety-one branched dendritic spines were traced through serial sections, and the different branches never synapsed with the same presynaptic bouton. Projections from spines, called "spinules," have been thought to extend from perforations in the postsynaptic density (PSD), thereby dividing the presynaptic bouton. Forty-six spinules were traced, and only 13\% emerged from perforations in the PSD. Most spinules emerged from the edges of nonperforated PSDs, or from spine necks, where they extended into boutons that were not presynaptic to the spine. In summary, these morphological characteristics are inconsistent with synapse and spine splitting. An alternative is discussed whereby perforated synapses and spinules are transient components of synaptic activation, and branched spines appear from synapses forming in close proximity to one another.}, Author = {K. E. Sorra and J. C. Fiala and K. M. Harris}, Journal = {J Comp Neurol}, Keywords = {Kristen Harris}, Month = {Aug}, Number = {2}, Pages = {225-40}, Title = {{Critical assessment of the involvement of perforations, spinules, and spine branching in hippocampal synapse formation.}}, Volume = {398}, Year = {1998}} @article{Sorra2000, Annote = {There has been an explosion of new information on the neurobiology of dendritic spines in synaptic signaling, integration, and plasticity. Novel imaging and analytical techniques have provided important new insights into dendritic spine structure and function. Results are accumulating across many disciplines, and a step toward consolidating some of this work has resulted in Dendritic Spines of the Hippocampus. Leaders in the field provide a discussion at the level of advanced under-graduates, with sufficient detail to be a contemporary resource for research scientists. Critical reviews are presented on topics ranging from spine structure, formation, and maintenance, to molecular composition, plasticity, and the role of spines in learning and memory. Dendritic Spines of the Hippocampus provides a timely discussion of our current understanding of form and function at these excitatory synapses. We asked authors to include areas of controversy in their papers so as to distinguish results that are generally agreed upon from those where multiple interpretations are possible. We thank the contributors for their insights and thoughtful discussions. In this paper we provide background on the structure, composition, function, development, plasticity, and pathology of hippocampal dendritic spines. In addition, we highlight where each of these subjects will be elaborated upon in subsequent papers of this special issue of Hippocampus.}, Author = {K. E. Sorra and K. M. Harris}, Journal = {Hippocampus}, Keywords = {Kristen Harris, review}, Number = {5}, Pages = {501-11}, Title = {{Overview on the structure, composition, function, development, and plasticity of hippocampal dendritic spines.}}, Volume = {10}, Year = {2000}} @article{Sorra1998b, Annote = {Long-term potentiation (LTP) is an important model for examining synaptic mechanisms of learning and memory. A key question is whether the enhanced synaptic transmission occurring with LTP involves the addition of new synapses, the enlargement of existing synapses, or a redistribution in synaptic weight among synapses. Two experimental designs were used to address this question. In the first experimental design three conditions were evaluated across hippocampal slices maintained in vitro, including slices with LTP analyzed at 2 hr post-tetanus, slices tetanized in the presence of APV, and control slices receiving test stimulation only. In the second experimental design independent LTP and control (low-frequency stimulation) sites were examined. Synapse density was estimated by an unbiased volume sampling procedure. Synapse size was computed by three-dimensional reconstruction from serial electron microscopy (EM). Serial EM also was used to compute synapse number per unit length of dendrite. In both experimental designs there were no significant effects of LTP on total synapse number, on the distribution of different types of synapses (thin, mushroom, stubby, or branched dendritic spines and macular, perforated, or segmented postsynaptic densities), on the frequency of shaft synapses, nor on the relative proportion of single or multiple synapse axonal boutons. There was also no increase in synapse size. These results suggest that LTP does not cause an overall formation of new synapses nor an enlargement of synapses at 2 hr post-tetanus in hippocampal area CA1, and these results support the hypothesis that LTP could involve a redistribution of synaptic weights among existing synapses.}, Author = {K. E. Sorra and K. M. Harris}, Journal = {J Neurosci}, Keywords = {Kristen Harris}, Month = {Jan}, Number = {2}, Pages = {658-71}, Title = {{Stability in synapse number and size at 2 hr after long-term potentiation in hippocampal area CA1.}}, Volume = {18}, Year = {1998}} @article{Steigerwald2000, Annote = {NMDA receptors interact via the extended intracellular C-terminal domain of the NR2 subunits with constituents of the postsynaptic density for purposes of retention, clustering, and functional regulation at central excitatory synapses. To examine the role of the C-terminal domain of NR2A in the synaptic localization and function of NR2A-containing NMDA receptors in hippocampal Schaffer collateral-CA1 pyramidal cell synapses, we analyzed mice which express NR2A only in its C-terminally truncated form. In CA1 cell somata, the levels, activation, and deactivation kinetics of extrasynaptic NMDA receptor channels were comparable in wild-type and mutant NR2A(Delta)(C/)(Delta)(C) mice. At CA1 cell synapses, however, the truncated receptors were less concentrated than their full-length counterparts, as indicated by immunodetection in cultured neurons, synaptosomes, and postsynaptic densities. In the mutant, the NMDA component of evoked EPSCs was reduced in a developmentally progressing manner and was even more reduced in miniature EPSCs (mEPSCs) elicited by spontaneous glutamate release. Moreover, pharmacologically isolated NMDA currents evoked by synaptic stimulation had longer latencies and displayed slower rise and decay times, even in the presence of an NR2B-specific antagonist. These data strongly suggest that the C-terminal domain of NR2A subunits is important for the precise synaptic arrangement of NMDA receptors.}, Author = {F. Steigerwald and T. W. Schulz and L. T. Schenker and M. B. Kennedy and P. H. Seeburg and G. Kohr}, Journal = {J Neurosci}, Keywords = {Kennedy}, Month = {Jun}, Number = {12}, Pages = {4573-81}, Title = {{C-Terminal truncation of NR2A subunits impairs synaptic but not extrasynaptic localization of NMDA receptors.}}, Volume = {20}, Year = {2000}} @article{Stevens2003, Annote = {Synaptotagmin is a synaptic vesicle protein that has been proposed to be the calcium sensor responsible for fast neurotransmitter release at synapses. Synaptotagmin's two C2 domains, C2A and C2B, each provide a calcium binding pocket lined with negative charges contributed by five conserved aspartates. We find that even when all of C2A's conserved aspartates are neutralized by replacement with asparagines, neurotransmitter release still occurs at hippocampal synapses in culture. Because exocytosis continues to be dependent on extracellular calcium concentration, the C2A domain cannot represent the entire calcium sensor. C2A does appear to be part of the calcium sensor, however, because substitution of D232 alters the calcium dependence of release, perhaps by reducing the number of calcium ions that must bind to trigger exocytosis. We conclude that neutralization of the negative charge at D232 by coordination of a calcium ion is necessary--but not sufficient--for fast neurotransmission at mammalian CNS synapses.}, Author = {C. F. Stevens and J. M. Sullivan}, Journal = {Neuron}, Month = {Jul}, Number = {2}, Pages = {299-308}, Title = {{The synaptotagmin C2A domain is part of the calcium sensor controlling fast synaptic transmission.}}, Volume = {39}, Year = {2003}} @article{Sweatt2001, Annote = {The mitogen-activated protein kinase (MAP kinase, MAPK) cascade, as the name implies, was originally discovered as a critical regulator of cell division and differentiation. As further details of this signaling cascade were worked out, it became clear that the MAPK cascade is in fact a prototype for a family of signaling cascades that share the motif of three serially linked kinases regulating each other by sequential phosphorylation. Thus, a revised nomenclature arose that uses the term MAPK to refer to the entire superfamily of signaling cascades (comprising the erks, the JNKs and the p38 stress activated protein kinases), and specifies the prototype MAPK as the extracellular signal-regulated kinase (erk). The two erk MAPK isoforms, p44 MAPK and p42 MAPK, are referred to as erk1 and erk2, respectively.The erks are abundantly expressed in neurons in the mature central nervous system, raising the question of why the prototype molecular regulators of cell division and differentiation are present in these non-dividing, terminally differentiated neurons. This review will describe the beginnings of an answer to this question. Interestingly, the general model has begun to emerge that the erk signaling system has been co-opted in mature neurons to function in synaptic plasticity and memory. Moreover, recent insights have led to the intriguing prospect that these molecules serve as biochemical signal integrators and molecular coincidence detectors for coordinating responses to extracellular signals in neurons. In this review I will first outline the essential components of this signal transduction cascade, and briefly describe recent results implicating the erks in mammalian synaptic plasticity and learning. I will then proceed to outline recent results implicating the erks as molecular signal integrators and, potentially, coincidence detectors. Finally, I will speculate on what the critical downstream effectors of the erks are in neurons, and how they might provide a readout of the integrated signal.}, Author = {J. D. Sweatt}, Journal = {J Neurochem}, Month = {Jan}, Number = {1}, Pages = {1-10}, Title = {{The neuronal MAP kinase cascade: a biochemical signal integration system subserving synaptic plasticity and memory.}}, Volume = {76}, Year = {2001}} @article{Takagi2000, Annote = {The postsynaptic density (PSD) is a cytoskeletal specialization involved in the anchoring of neurotransmitter receptors and in regulating the response of postsynaptic neurons to synaptic stimulation. The postsynaptic protein PSD-95 binds to NMDA receptor subunits NR2A and NR2B and to signaling molecules such as neuronal nitric oxide synthase and p135synGAP. We investigated the effects of transient cerebral ischemia on protein interactions involving PSD-95 and the NMDA receptor in the rat hippocampus. Ischemia followed by reperfusion resulted in a decrease in the solubility of the NMDA receptor and PSD-95 in 1\% sodium deoxycholate, the decrease being greater in the vulnerable CA1 hippocampal subfield than in the less sensitive CA3/dentate gyrus regions. Solubilization of the kainic acid receptor GluR6/7 and the PSD-95 binding proteins, neuronal nitric oxide synthase and p135synGAP, also decreased following ischemia. The association between PSD-95 and NR2A and NR2B, as indicated by coimmunoprecipitation, was less in postischemic samples than in sham-operated controls. Ischemia also resulted in a decrease in the size of protein complexes containing PSD-95, but had only a small effect on the size distribution of complexes containing the NMDA receptor. The results indicate that molecular interactions involving PSD-95 and the NMDA receptor are modified by an ischemic challenge.}, Author = {N. Takagi and R. Logan and L. Teves and M. C. Wallace and J. W. Gurd}, Journal = {J Neurochem}, Month = {Jan}, Number = {1}, Pages = {169-78}, Title = {{Altered interaction between PSD-95 and the NMDA receptor following transient global ischemia.}}, Volume = {74}, Year = {2000}} @article{Tang2001, Annote = {RNAs are present in dendrites and may be used for local protein synthesis in response to synaptic activity. To begin to understand dendritic RNA targeting, we cloned a rat homolog of staufen, a Drosophila gene that participates in mRNA targeting during development. In hippocampal neurons, rat staufen protein displays a microtubule-dependent somatodendritic distribution pattern that overlaps with dendritic RNAs. To determine whether r-staufen is required for dendritic RNA targeting, we constructed a mutant version containing the RNA binding domains (stau-RBD) but lacking the C-terminal portion potentially involved in dendritic targeting. Stau-RBD expression was restricted to the cell bodies and proximal dendrites. Expression of stau-RBD significantly decreased, while overexpression of wild-type r-staufen increased, the amount of dendritic mRNA. Taken together, these results suggest that the rat staufen protein plays an important role in the delivery of RNA to dendrites.}, Author = {S. J. Tang and D. Meulemans and L. Vazquez and N. Colaco and E. Schuman}, Journal = {Neuron}, Month = {Nov}, Number = {3}, Pages = {463-75}, Title = {{A role for a rat homolog of staufen in the transport of RNA to neuronal dendrites.}}, Volume = {32}, Year = {2001}} @article{Tashiro2000, Annote = {Dendritic spines mediate most excitatory transmission in the mammalian CNS and have been traditionally considered stable structures. Following the suggestion that spines may 'twitch', it has been recently shown that spines are capable of rapid morphological rearrangements. Because of the role of the small GTPases from the Rho family in controlling neuronal morphogenesis, we investigated the effects of several members of this biochemical signaling pathway in the maintenance of the morphology of extant dendritic spines by combining biolistic transfection of pyramidal neurons in cultured cortical and hippocampal slices with two-photon microscopy. We find a variety of effects on the density and morphology of dendritic spines by expressing either constitutively active or dominant negative forms of several small GTPases of the Rho family, by blocking the entire pathway with Clostridium difficile toxin B or by blocking Rho with C3 transferase. We propose a model where Rac promotes spine formation, while Rho prevents it. We conclude that the small GTPases provide antagonistic control mechanisms of spine maintenance in pyramidal neurons.}, Author = {A. Tashiro and A. Minden and R. Yuste}, Journal = {Cereb Cortex}, Month = {Oct}, Number = {10}, Pages = {927-38}, Title = {{Regulation of dendritic spine morphology by the rho family of small GTPases: antagonistic roles of Rac and Rho.}}, Volume = {10}, Year = {2000}} @article{Thomas2004, Author = {G. M. Thomas and R. L. Huganir}, Journal = {Nat Rev Neurosci}, Month = {Mar}, Number = {3}, Pages = {173-83}, Title = {{MAPK cascade signalling and synaptic plasticity.}}, Volume = {5}, Year = {2004}} @article{Tomoda2004, Annote = {Previous studies showed that the serine/threonine kinase Unc51.1 is one of the earliest genes in neuronal differentiation and is required for granule cell axon formation. To examine the mechanism of Unc51.1 regulation of axon extension, we have identified two direct binding partners. The first, SynGAP, a negative regulator of Ras, is expressed within axons and growth cones of developing granule cells. Overexpression of SynGAP blocks neurite outgrowth by a mechanism that involves Ras-like GTPase cascade. The second binding partner is a PDZ domain-containing scaffolding protein, Syntenin, that binds Rab5 GTPase, the activity of which is attenuated by SynGAP. Thus, our results demonstrate that the Unc51.1-containing protein complex governs axon formation via Ras-like GTPase signaling and through regulation of the Rab5-mediated endocytic pathways within developing axons.}, Author = {T. Tomoda and J. H. Kim and C. Zhan and M. E. Hatten}, Journal = {Genes Dev}, Month = {Mar}, Number = {5}, Pages = {541-58}, Title = {{Role of Unc51.1 and its binding partners in CNS axon outgrowth.}}, Volume = {18}, Year = {2004}} @article{Tybulewicz1991, Annote = {The c-abl proto-oncogene, which encodes a cytoplasmic protein-tyrosine kinase, is expressed throughout murine gestation and ubiquitously in adult mouse tissues. However, its levels are highest in thymus, spleen, and testes. To examine the in vivo role of c-abl, the gene was disrupted in embryonic stem cells, and the resulting genetically modified cells were used to establish a mouse strain carrying the mutation. Most mice homozygous for the c-abl mutation became runted and died 1 to 2 weeks after birth. In addition, many showed thymic and splenic atrophy and a T and B cell lymphopenia.}, Author = {V. L. Tybulewicz and C. E. Crawford and P. K. Jackson and R. T. Bronson and R. C. Mulligan}, Journal = {Cell}, Month = {Jun}, Number = {7}, Pages = {1153-63}, Title = {{Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene.}}, Volume = {65}, Year = {1991}} @article{Walikonis2000, Annote = {Our understanding of the organization of postsynaptic signaling systems at excitatory synapses has been aided by the identification of proteins in the postsynaptic density (PSD) fraction, a subcellular fraction enriched in structures with the morphology of PSDs. In this study, we have completed the identification of most major proteins in the PSD fraction with the use of an analytical method based on mass spectrometry coupled with searching of the protein sequence databases. At least one protein in each of 26 prominent protein bands from the PSD fraction has now been identified. We found 7 proteins not previously known to be constituents of the PSD fraction and 24 that had previously been associated with the PSD by other methods. The newly identified proteins include the heavy chain of myosin-Va (dilute myosin), a motor protein thought to be involved in vesicle trafficking, and the mammalian homolog of the yeast septin protein cdc10, which is important for bud formation in yeast. Both myosin-Va and cdc10 are threefold to fivefold enriched in the PSD fraction over brain homogenates. Immunocytochemical localization of myosin-Va in cultured hippocampal neurons shows that it partially colocalizes with PSD-95 at synapses and is also diffusely localized in cell bodies, dendrites, and axons. Cdc10 has a punctate distribution in cell bodies and dendrites, with some of the puncta colocalizing with PSD-95. The results support a role for myosin-Va in transport of materials into spines and for septins in the formation or maintenance of spines.}, Author = {R. S. Walikonis and O. N. Jensen and M. Mann and J. r. Provance D.W. and J. A. Mercer and M. B. Kennedy}, Journal = {J Neurosci}, Month = {Jun}, Number = {11}, Pages = {4069-80}, Title = {{Identification of proteins in the postsynaptic density fraction by mass spectrometry.}}, Volume = {20}, Year = {2000}} @article{Walter2000, Annote = {We physically mapped the centromeric part of the BN rat MHC (RT1n haplotype) in a contig of overlapping P1-derived artificial chromosome (PAC) clones encompassing about 300 kb. The following genes were identified and ordered as: (Syngap, Hset, Daxx, Bing1)-Tapbp-Rgl2-Ke2-Bing4-B3galt4- Rps18-Sacm2l-RT1-A1-RT1-A2-RT1-A3-Ring1-Ring2-++ +Ke4-Rxrb-Col11a2-RT1-Hb-Ring3-RT1-DMb. Thus, in contrast to other RT1 haplotypes, RT1n contains three class I genes, RT1-A1, RT1-A2, and RT1-A3, mapping between the Sacm2l and Ring1 genes. Comparisons of the sequences flanking the Sacm2L and Ring1 genes in rat, human, and mouse suggest that the class I gene-containing region was inserted between these genes in rat and mouse at a similar position. Thus, this insertion is likely to have occurred in a common ancestor of these rodents, although the presence of a site particularly permissive for insertions cannot be excluded.}, Author = {L. Walter and E. Gunther}, Journal = {Immunogenetics}, Month = {Aug}, Number = {10}, Pages = {829-37}, Title = {{Physical mapping and evolution of the centromeric class I gene-containing region of the rat MHC.}}, Volume = {51}, Year = {2000}} @article{Wu2001, Annote = {Memory storage in mammalian neurons probably depends on both biochemical events and morphological alterations in dendrites. Here we report an activity-dependent stabilization of the MAP kinase (MAPK) pathway, prominent in hippocampal dendrites. The longevity of the signal in these dendrites was increased to hours when multiple spaced stimuli were used. Likewise, spaced stimuli and MAPK activation were critical for protrusion of new dendritic filopodia that also remained stable for hours. Our experiments define a new role for stimulus-specific responses of MAPK signaling in activity-dependent neuronal plasticity. The local biochemical signaling in dendrites complements MAPK signaling in gene expression. Together, these processes may support long-lasting behavioral changes.}, Author = {G. Y. Wu and K. Deisseroth and R. W. Tsien}, Journal = {Nat Neurosci}, Month = {Feb}, Number = {2}, Pages = {151-158}, Title = {{Spaced stimuli stabilize MAPK pathway activation and its effects on dendritic morphology.}}, Volume = {4}, Year = {2001}} @article{Xiao2000, Annote = {The proteins of the Homer family bind to proline-rich sequences in group I metabotropic glutamate receptors, inositol trisphosphate receptors, ryanodine receptors, and Shank family proteins. Homer proteins also self associate and function as adaptors to couple interacting proteins. Recent observations indicate a role for Homer complexes in signal transduction, synaptogenesis and receptor trafficking.}, Author = {B. Xiao and J. C. Tu and P. F. Worley}, Journal = {Curr Opin Neurobiol}, Month = {Jun}, Number = {3}, Pages = {370-374}, Title = {{Homer: a link between neural activity and glutamate receptor function.}}, Volume = {10}, Year = {2000}} @article{Ye2000, Annote = {The PDZ domain-containing proteins, such as PSD-95 and GRIP, have been suggested to be involved in the targeting of glutamate receptors, a process that plays a critical role in the efficiency of synaptic transmission and plasticity. To address the molecular mechanisms underlying AMPA receptor synaptic localization, we have identified several GRIP-associated proteins (GRASPs) that bind to distinct PDZ domains within GRIP. GRASP-1 is a neuronal rasGEF associated with GRIP and AMPA receptors in vivo. Overexpression of GRASP-1 in cultured neurons specifically reduced the synaptic targeting of AMPA receptors. In addition, the subcellular distribution of both AMPA receptors and GRASP-1 was rapidly regulated by the activation of NMDA receptors. These results suggest that GRASP-1 may regulate neuronal ras signaling and contribute to the regulation of AMPA receptor distribution by NMDA receptor activity.}, Author = {B. Ye and D. Liao and X. Zhang and P. Zhang and H. Dong and R. L. Huganir}, Journal = {Neuron}, Month = {Jun}, Number = {3}, Pages = {603-17}, Title = {{GRASP-1: a neuronal RasGEF associated with the AMPA receptor/GRIP complex.}}, Volume = {26}, Year = {2000}} @article{Yuste2004, Author = {R. Yuste and T. Bonhoeffer}, Journal = {Nat Rev Neurosci}, Month = {Jan}, Number = {1}, Pages = {24-34}, Title = {{Genesis of dendritic spines: insights from ultrastructural and imaging studies.}}, Volume = {5}, Year = {2004}} @article{Zhang1999, Annote = {Synaptic NMDA-type glutamate receptors are anchored to the second of three PDZ (PSD-95/Discs large/ZO-1) domains in the postsynaptic density (PSD) protein PSD-95. Here, we report that citron, a protein target for the activated form of the small GTP-binding protein Rho, preferentially binds the third PDZ domain of PSD-95. In GABAergic neurons from the hippocampus, citron forms a complex with PSD-95 and is concentrated at the postsynaptic side of glutamatergic synapses. Citron is expressed only at low levels in glutamatergic neurons in the hippocampus and is not detectable at synapses onto these neurons. In contrast to citron, p135 SynGAP, an abundant synaptic Ras GTPase-activating protein that can bind to all three PDZ domains of PSD-95, and Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) are concentrated postsynaptically at glutamatergic synapses on glutamatergic neurons. CaM kinase II is not expressed and p135 SynGAP is expressed in less than half of hippocampal GABAergic neurons. Segregation of citron into inhibitory neurons does not occur in other brain regions. For example, citron is expressed at high levels in most thalamic neurons, which are primarily glutamatergic and contain CaM kinase II. In several other brain regions, citron is present in a subset of neurons that can be either GABAergic or glutamatergic and can sometimes express CaM kinase II. Thus, in the hippocampus, signal transduction complexes associated with postsynaptic NMDA receptors are different in glutamatergic and GABAergic neurons and are specialized in a way that is specific to the hippocampus.}, Author = {W. Zhang and L. Vazquez and M. Apperson and M. B. Kennedy}, Journal = {J Neurosci}, Month = {Jan}, Number = {1}, Pages = {96-108}, Title = {{Citron binds to PSD-95 at glutamatergic synapses on inhibitory neurons in the hippocampus.}}, Volume = {19}, Year = {1999}} @article{Zhu2002b, Author = {J. J. Zhu and R. Malinow}, Journal = {Nat Neurosci}, Month = {Jun}, Number = {6}, Pages = {513-514}, Title = {{Acute versus chronic NMDA receptor blockade and synaptic AMPA receptor delivery.}}, Volume = {5}, Year = {2002}} @article{Zhu2002, Annote = {Recent studies show that AMPA receptor (-R) trafficking is important in synaptic plasticity. However, the signaling controlling this trafficking is poorly understood. Small GTPases have diverse neuronal functions and their perturbation is responsible for several mental disorders. Here, we examine the small GTPases Ras and Rap in the postsynaptic signaling underlying synaptic plasticity. We show that Ras relays the NMDA-R and CaMKII signaling that drives synaptic delivery of AMPA-Rs during long-term potentiation. In contrast, Rap mediates NMDA-R-dependent removal of synaptic AMPA-Rs that occurs during long-term depression. Ras and Rap exert their effects on AMPA-Rs that contain different subunit composition. Thus, Ras and Rap, whose activity can be controlled by postsynaptic enzymes, serve as independent regulators for potentiating and depressing central synapses.}, Author = {J. J. Zhu and Y. Qin and M. Zhao and L. Van Aelst and R. Malinow}, Journal = {Cell}, Month = {Aug}, Number = {4}, Pages = {443-55}, Title = {{Ras and Rap control AMPA receptor trafficking during synaptic plasticity.}}, Volume = {110}, Year = {2002}}