Activity-dependent regulation of synaptic strength by PSD-95 in CA1 neurons.

CaMKII and PSD-95 are the two most abundant postsynaptic proteins in the postsynaptic density (PSD). Overexpression of either can dramatically increase synaptic strength and saturate long-term potentiation (LTP). To do so, CaMKII must be activated, but the same is not true for PSD-95; expressing wild-type PSD-95 is sufficient. This raises the question of whether PSD-95's effects are simply an equilibrium process [increasing the number of AMPA receptor (AMPAR) slots] or whether activity is somehow involved. To examine this question, we blocked activity in cultured hippocampal slices with TTX and found that the effects of PSD-95 overexpression were greatly reduced. We next studied the type of receptors involved. The effects of PSD-95 were prevented by antagonists of group I metabotropic glutamate receptors (mGluRs) but not by antagonists of ionotropic glutamate receptors. The inhibition of PSD-95-induced strengthening was not simply a result of inhibition of PSD-95 synthesis. To understand the mechanisms involved, we tested the role of CaMKII. Overexpression of a CaMKII inhibitor, CN19, greatly reduced the effect of PSD-95. We conclude that PSD-95 cannot itself increase synaptic strength simply by increasing the number of AMPAR slots; rather, PSD-95's effects on synaptic strength require an activity-dependent process involving mGluR and CaMKII.

[1]  S. Raghavachari,et al.  Quantitative estimates of the cytoplasmic, PSD, and NMDAR-bound pools of CaMKII in dendritic spines , 2011, Brain Research.

[2]  John Lisman,et al.  Role of the CaMKII/NMDA Receptor Complex in the Maintenance of Synaptic Strength , 2011, The Journal of Neuroscience.

[3]  Magdalena G. Wutte,et al.  Calcium/Calmodulin-Dependent Protein Kinase II Mediates Group I Metabotropic Glutamate Receptor-Dependent Protein Synthesis and Long-Term Depression in Rat Hippocampus , 2011, The Journal of Neuroscience.

[4]  G. Turrigiano,et al.  PSD-95 and PSD-93 Play Critical But Distinct Roles in Synaptic Scaling Up and Down , 2011, The Journal of Neuroscience.

[5]  R. Petralia,et al.  MAGUKs, Synaptic Development, and Synaptic Plasticity , 2011, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[6]  Weifeng Xu,et al.  PSD-95-like membrane associated guanylate kinases (PSD-MAGUKs) and synaptic plasticity , 2011, Current Opinion in Neurobiology.

[7]  John E. Lisman,et al.  Calmodulin as a Direct Detector of Ca2+ Signals , 2011, Nature Neuroscience.

[8]  R. Petralia,et al.  Differential localization of SAP102 and PSD-95 is revealed in hippocampal spines using super-resolution light microscopy , 2011, Communicative & integrative biology.

[9]  Lu Chen,et al.  Fragile X Protein FMRP Is Required for Homeostatic Plasticity and Regulation of Synaptic Strength by Retinoic Acid , 2010, The Journal of Neuroscience.

[10]  Paul De Koninck,et al.  CaMKII control of spine size and synaptic strength: Role of phosphorylation states and nonenzymatic action , 2010, Proceedings of the National Academy of Sciences.

[11]  Paul De Koninck,et al.  Autonomous CaMKII Can Promote either Long-Term Potentiation or Long-Term Depression, Depending on the State of T305/T306 Phosphorylation , 2010, The Journal of Neuroscience.

[12]  Thomas G. Oertner,et al.  Differential distribution of endoplasmic reticulum controls metabotropic signaling and plasticity at hippocampal synapses , 2009, Proceedings of the National Academy of Sciences.

[13]  Seok-Jin R. Lee,et al.  Activation of CaMKII in single dendritic spines during long-term potentiation , 2009, Nature.

[14]  R. Nicoll,et al.  Differential trafficking of AMPA and NMDA receptors by SAP102 and PSD-95 underlies synapse development , 2008, Proceedings of the National Academy of Sciences.

[15]  G. Knott,et al.  PSD-95 promotes synaptogenesis and multiinnervated spine formation through nitric oxide signaling , 2008, The Journal of cell biology.

[16]  R. Malenka,et al.  Destabilization of the Postsynaptic Density by PSD-95 Serine 73 Phosphorylation Inhibits Spine Growth and Synaptic Plasticity , 2008, Neuron.

[17]  Lu Chen,et al.  Synaptic Signaling by All-Trans Retinoic Acid in Homeostatic Synaptic Plasticity , 2008, Neuron.

[18]  Michael D. Ehlers,et al.  Structural plasticity with preserved topology in the postsynaptic protein network , 2008, Proceedings of the National Academy of Sciences.

[19]  Xiaobing Chen,et al.  Organization of the core structure of the postsynaptic density , 2008, Proceedings of the National Academy of Sciences.

[20]  Hyung-Bae Kwon,et al.  Long-Term Potentiation Selectively Expressed by NMDA Receptors at Hippocampal Mossy Fiber Synapses , 2008, Neuron.

[21]  John Lisman,et al.  Synaptic Strength of Individual Spines Correlates with Bound Ca2+–Calmodulin-Dependent Kinase II , 2007, The Journal of Neuroscience.

[22]  J. Port,et al.  Dual mechanism of a natural CaMKII inhibitor. , 2007, Molecular biology of the cell.

[23]  M. Sheng,et al.  Synaptic Accumulation of PSD-95 and Synaptic Function Regulated by Phosphorylation of Serine-295 of PSD-95 , 2007, Neuron.

[24]  Ivan Soltesz,et al.  Homeostatic Plasticity Studied Using In Vivo Hippocampal Activity-Blockade: Synaptic Scaling, Intrinsic Plasticity and Age-Dependence , 2007, PloS one.

[25]  Christina Gross,et al.  Dysregulated Metabotropic Glutamate Receptor-Dependent Translation of AMPA Receptor and Postsynaptic Density-95 mRNAs at Synapses in a Mouse Model of Fragile X Syndrome , 2007, The Journal of Neuroscience.

[26]  J. Lisman,et al.  Reversal of Synaptic Memory by Ca2+/Calmodulin-Dependent Protein Kinase II Inhibitor , 2007, The Journal of Neuroscience.

[27]  S. Grant,et al.  A new function for the fragile X mental retardation protein in regulation of PSD-95 mRNA stability , 2007, Nature Neuroscience.

[28]  R. Malinow,et al.  PSD-95 is required for activity-driven synapse stabilization , 2007, Proceedings of the National Academy of Sciences.

[29]  N. Matsuki,et al.  Metastability of Active CA3 Networks , 2007, The Journal of Neuroscience.

[30]  Karel Svoboda,et al.  Rapid Redistribution of Synaptic PSD-95 in the Neocortex In Vivo , 2006, PLoS biology.

[31]  M. di Luca,et al.  Calcium–calmodulin‐dependent protein kinase II phosphorylation modulates PSD‐95 binding to NMDA receptors , 2006, The European journal of neuroscience.

[32]  Lars Funke,et al.  Synapse-Specific and Developmentally Regulated Targeting of AMPA Receptors by a Family of MAGUK Scaffolding Proteins , 2006, Neuron.

[33]  Robert C. Malenka,et al.  Alternative N-Terminal Domains of PSD-95 and SAP97 Govern Activity-Dependent Regulation of Synaptic AMPA Receptor Function , 2006, Neuron.

[34]  C. Hoogenraad,et al.  Relative and Absolute Quantification of Postsynaptic Density Proteome Isolated from Rat Forebrain and Cerebellum*S , 2006, Molecular & Cellular Proteomics.

[35]  R. Malinow,et al.  NMDA Receptor Subunit Composition Controls Synaptic Plasticity by Regulating Binding to CaMKII , 2005, Neuron.

[36]  Xiaobing Chen,et al.  Mass of the postsynaptic density and enumeration of three key molecules. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[37]  M Neal Waxham,et al.  A Mechanism for Ca2+/Calmodulin-Dependent Protein Kinase II Clustering at Synaptic and Nonsynaptic Sites Based on Self-Association , 2005, The Journal of Neuroscience.

[38]  P. Sanna,et al.  The metabotropic glutamate receptor 5 is necessary for late-phase long-term potentiation in the hippocampal CA1 region , 2004, Brain Research.

[39]  M. Sheng,et al.  PDZ domain proteins of synapses , 2004, Nature Reviews Neuroscience.

[40]  Stéphanie Ratté,et al.  Synapse‐specific mGluR1‐dependent long‐term potentiation in interneurones regulates mouse hippocampal inhibition , 2004, The Journal of physiology.

[41]  S. Nelson,et al.  Homeostatic plasticity in the developing nervous system , 2004, Nature Reviews Neuroscience.

[42]  R. Malinow,et al.  Postsynaptic Density 95 controls AMPA Receptor Incorporation during Long-Term Potentiation and Experience-Driven Synaptic Plasticity , 2004, The Journal of Neuroscience.

[43]  Peter K. Todd,et al.  The fragile X mental retardation protein is required for type-I metabotropic glutamate receptor-dependent translation of PSD-95 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[44]  R. Nicoll,et al.  Postsynaptic Density-95 Mimics and Occludes Hippocampal Long-Term Potentiation and Enhances Long-Term Depression , 2003, The Journal of Neuroscience.

[45]  Thomas Nevian,et al.  High-efficiency transfection of individual neurons using modified electrophysiology techniques , 2003, Journal of Neuroscience Methods.

[46]  Jean-Claude Béïque,et al.  PSD‐95 regulates synaptic transmission and plasticity in rat cerebral cortex , 2003, The Journal of physiology.

[47]  R. Nicoll,et al.  Direct interactions between PSD-95 and stargazin control synaptic AMPA receptor number , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[48]  Neal Sweeney,et al.  Synaptic Strength Regulated by Palmitate Cycling on PSD-95 , 2002, Cell.

[49]  J. Lisman,et al.  The molecular basis of CaMKII function in synaptic and behavioural memory , 2002, Nature Reviews Neuroscience.

[50]  Kurt Haas,et al.  Single-Cell Electroporationfor Gene Transfer In Vivo , 2001, Neuron.

[51]  J. Zhu,et al.  Postnatal synaptic potentiation: Delivery of GluR4-containing AMPA receptors by spontaneous activity , 2000, Nature Neuroscience.

[52]  Y. Watanabe,et al.  Inhibition of neuronal nitric-oxide synthase by calcium/ calmodulin-dependent protein kinase IIalpha through Ser847 phosphorylation in NG108-15 neuronal cells. , 2000, The Journal of biological chemistry.

[53]  R. Malinow,et al.  Driving AMPA receptors into synapses by LTP and CaMKII: requirement for GluR1 and PDZ domain interaction. , 2000, Science.

[54]  W. N. Ross,et al.  Synergistic Release of Ca2+ from IP3-Sensitive Stores Evoked by Synaptic Activation of mGluRs Paired with Backpropagating Action Potentials , 1999, Neuron.

[55]  H. Yokokura,et al.  Regulation of Neuronal Nitric-oxide Synthase by Calmodulin Kinases* , 1999, The Journal of Biological Chemistry.

[56]  Z. Bortolotto,et al.  The potent mGlu receptor antagonist LY341495 identifies roles for both cloned and novel mGlu receptors in hippocampal synaptic plasticity , 1998, Neuropharmacology.

[57]  T. Soderling,et al.  Characterization of a calmodulin kinase II inhibitor protein in brain. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[58]  Niraj S. Desai,et al.  Activity-dependent scaling of quantal amplitude in neocortical neurons , 1998, Nature.

[59]  Ayae Kinoshita,et al.  Differential Presynaptic Localization of Metabotropic Glutamate Receptor Subtypes in the Rat Hippocampus , 1997, The Journal of Neuroscience.

[60]  R Lujan,et al.  Perisynaptic Location of Metabotropic Glutamate Receptors mGluR1 and mGluR5 on Dendrites and Dendritic Spines in the Rat Hippocampus , 1996, The European journal of neuroscience.

[61]  R. Petralia,et al.  The metabotropic glutamate receptors, MGLUR2 and MGLUR3, show unique postsynaptic, presynaptic and glial localizations , 1996, Neuroscience.

[62]  R. Nicoll,et al.  Calcium/calmodulin-dependent kinase II and long-term potentiation enhance synaptic transmission by the same mechanism. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[63]  R. Malinow,et al.  Potentiated transmission and prevention of further LTP by increased CaMKII activity in postsynaptic hippocampal slice neurons. , 1994, Science.

[64]  Daniel Johnston,et al.  Endogenous nature of spontaneous bursting in hippocampal pyramidal neurons , 1981, Cellular and Molecular Neurobiology.

[65]  Dominique Muller,et al.  Activity-dependent PSD formation and stabilization of newly formed spines in hippocampal slice cultures. , 2008, Cerebral cortex.

[66]  Norio Matsuki,et al.  Metastability of Active CA 3 Networks , 2007 .

[67]  杉山 佳子.  Determination of absolute protein numbers in single synapses by a GFP-based calibration technique , 2005 .

[68]  M. Ehlers.  Activity level controls postsynaptic composition and signaling via the ubiquitin-proteasome system , 2003, Nature neuroscience.