Integration of biochemical signalling in spines

Short-term and long-term changes in the strength of synapses in neural networks underlie working memory and long-term memory storage in the brain. These changes are regulated by many biochemical signalling pathways in the postsynaptic spines of excitatory synapses. Recent findings about the roles and regulation of the small GTPases Ras, Rap and Rac in spines provide new insights into the coordination and cooperation of different pathways to effect synaptic plasticity. Here, we present an initial working representation of the interactions of five signalling cascades that are usually studied individually. We discuss their integrated function in the regulation of postsynaptic plasticity.

[1]  D. Selkoe.  Alzheimer's Disease Is a Synaptic Failure , 2002, Science.

[2]  M. Kennedy,et al.  A role for synGAP in regulating neuronal apoptosis , 2005, The European journal of neuroscience.

[3]  Tiffany Lyle,et al.  Modulation of NMDA Receptor-Dependent Calcium Influx and Gene Expression Through EphB Receptors , 2005 .

[4]  M. Waterfield,et al.  Synthesis and function of 3-phosphorylated inositol lipids. , 2001, Annual review of biochemistry.

[5]  M. Kennedy,et al.  Signal-processing machines at the postsynaptic density. , 2000, Science.

[6]  Richard L. Huganir,et al.  Postsynaptic organisation and regulation of excitatory synapses , 2000, Nature Reviews Neuroscience.

[7]  A M Graybiel,et al.  A family of cAMP-binding proteins that directly activate Rap1. , 1998, Science.

[8]  J. Avruch,et al.  Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. , 2001, Physiological reviews.

[9]  R. Huganir,et al.  Rapid Induction of Dendritic Spine Morphogenesis by trans-Synaptic EphrinB-EphB Receptor Activation of the Rho-GEF Kalirin , 2003, Neuron.

[10]  D. Clapham,et al.  SynGAP-MUPP1-CaMKII Synaptic Complexes Regulate p38 MAP Kinase Activity and NMDA Receptor- Dependent Synaptic AMPA Receptor Potentiation , 2004, Neuron.

[11]  P. J. Sjöström,et al.  Spike timing, calcium signals and synaptic plasticity , 2002, Current Opinion in Neurobiology.

[12]  KM Harris,et al.  Dendritic spines of CA 1 pyramidal cells in the rat hippocampus: serial electron microscopy with reference to their biophysical characteristics , 1989, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[13]  T. Soderling,et al.  Ca2+/calmodulin-kinase II enhances channel conductance of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate type glutamate receptors. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[14]  P. Warne,et al.  R-Ras can activate the phosphoinositide 3-kinase but not the MAP kinase arm of the Ras effector pathways , 1997, Current Biology.

[15]  R. Huganir,et al.  Targeting of PKA to Glutamate Receptors through a MAGUK-AKAP Complex , 2000, Neuron.

[16]  Y. Kaziro,et al.  Induction of Rac-Guanine Nucleotide Exchange Activity of Ras-GRF1/CDC25Mm following Phosphorylation by the Nonreceptor Tyrosine Kinase Src* , 2000, The Journal of Biological Chemistry.

[17]  Robert J. Lefkowitz,et al.  Role of c-Src Tyrosine Kinase in G Protein-coupled Receptorand Gβγ Subunit-mediated Activation of Mitogen-activated Protein Kinases* , 1996, The Journal of Biological Chemistry.

[18]  J. Stone,et al.  RasGRP, a Ras guanyl nucleotide- releasing protein with calcium- and diacylglycerol-binding motifs. , 1998, Science.

[19]  G L Johnson,et al.  Organization and regulation of mitogen-activated protein kinase signaling pathways. , 1999, Current opinion in cell biology.

[20]  G. Bokoch.  Biology of the p21-activated kinases. , 2003, Annual review of biochemistry.

[21]  Li-Huei Tsai,et al.  A decade of CDK5 , 2001, Nature Reviews Molecular Cell Biology.

[22]  R. Yuste,et al.  Morphological changes in dendritic spines associated with long-term synaptic plasticity. , 2001, Annual review of neuroscience.

[23]  T. Pawson,et al.  Signaling through scaffold, anchoring, and adaptor proteins. , 1997, Science.

[24]  J. Schrader,et al.  Ras and relatives--job sharing and networking keep an old family together. , 2002, Experimental hematology.

[25]  E. Quinlan,et al.  CPEB-Mediated Cytoplasmic Polyadenylation and the Regulation of Experience-Dependent Translation of α-CaMKII mRNA at Synapses , 1998, Neuron.

[26]  Y. Dan,et al.  Spike Timing-Dependent Plasticity of Neural Circuits , 2004, Neuron.

[27]  Ravi Iyengar,et al.  Modeling Signaling Networks , 2002, Science.

[28]  E. Elion,et al.  The Ste5p scaffold. , 2001, Journal of cell science.

[29]  C. Finch,et al.  Targeting small Aβ oligomers: the solution to an Alzheimer's disease conundrum? , 2001, Trends in Neurosciences.

[30]  R. Huganir,et al.  Characterization of Multiple Phosphorylation Sites on the AMPA Receptor GluR1 Subunit , 1996, Neuron.

[31]  Anirvan Ghosh,et al.  Calcium activation of Ras mediated by neuronal exchange factor Ras-GRF , 1995, Nature.

[32]  Steven P Gygi,et al.  Semiquantitative Proteomic Analysis of Rat Forebrain Postsynaptic Density Fractions by Mass Spectrometry* , 2004, Journal of Biological Chemistry.

[33]  P. Worley,et al.  Coupling of mGluR/Homer and PSD-95 Complexes by the Shank Family of Postsynaptic Density Proteins , 1999, Neuron.

[34]  D. Johnston,et al.  A Synaptically Controlled, Associative Signal for Hebbian Plasticity in Hippocampal Neurons , 1997, Science.

[35]  A. Graybiel,et al.  A Rap guanine nucleotide exchange factor enriched highly in the basal ganglia. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[36]  J. Garthwaite.  Glutamate, nitric oxide and cell-cell signalling in the nervous system , 1991, Trends in Neurosciences.

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

[38]  Michelle N. Ngo,et al.  Multiple EphB receptor tyrosine kinases shape dendritic spines in the hippocampus , 2003, The Journal of cell biology.

[39]  S. J. Martin,et al.  SynGAP Regulates ERK/MAPK Signaling, Synaptic Plasticity, and Learning in the Complex with Postsynaptic Density 95 and NMDA Receptor , 2002, The Journal of Neuroscience.

[40]  Kristen M Harris,et al.  Structural changes at dendritic spine synapses during long-term potentiation. , 2003, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[41]  C. Der,et al.  The Ras branch of small GTPases: Ras family members don't fall far from the tree. , 2000, Current opinion in cell biology.

[42]  Terrence J. Sejnowski,et al.  An MCell model of calcium dynamics and frequency-dependence of calmodulin activation in dendritic spines , 2001, Neurocomputing.

[43]  Takashi Kudo,et al.  Induction of neuronal death by ER stress in Alzheimer’s disease , 2004, Journal of Chemical Neuroanatomy.

[44]  M. Sheng,et al.  Regulation of Dendritic Spine Morphology by SPAR, a PSD-95-Associated RapGAP , 2001, Neuron.

[45]  M. Kennedy,et al.  A Synaptic Ras-GTPase Activating Protein (p135 SynGAP) Inhibited by CaM Kinase II , 1998, Neuron.

[46]  O. Steward,et al.  Compartmentalized Synthesis and Degradation of Proteins in Neurons , 2003, Neuron.

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

[48]  A. Graybiel,et al.  Guanine nucleotide exchange factors CalDAG‐GEFI and CalDAG‐GEFII are colocalized in striatal projection neurons , 2001, The Journal of comparative neurology.

[49]  R. Weinberg,et al.  Laminar Organization of the NMDA Receptor Complex within the Postsynaptic Density , 2001, The Journal of Neuroscience.

[50]  E. Huang,et al.  Trk receptors: roles in neuronal signal transduction. , 2003, Annual review of biochemistry.

[51]  E. Klann,et al.  Biochemical mechanisms for translational regulation in synaptic plasticity , 2004, Nature Reviews Neuroscience.

[52]  A. Matus,et al.  Actin-based plasticity in dendritic spines. , 2000, Science.

[53]  E. Quinlan,et al.  Postsynaptic Mechanisms for Bidirectional Control of MAP2 Phosphorylation by Glutamate Receptors , 1996, Neuron.

[54]  Mary B. Kennedy,et al.  Spine architecture and synaptic plasticity , 2005, Trends in Neurosciences.

[55]  F. Edwards,et al.  Anatomy and electrophysiology of fast central synapses lead to a structural model for long-term potentiation. , 1995, Physiological reviews.

[56]  D. Storm,et al.  Why calcium-stimulated adenylyl cyclases? , 2004, Physiology.

[57]  J. Colicelli,et al.  Human RAS Superfamily Proteins and Related GTPases , 2004, Science's STKE.

[58]  Ger J. A. Ramakers,et al.  Rho proteins, mental retardation and the cellular basis of cognition , 2002, Trends in Neurosciences.

[59]  E. Kandel,et al.  Rap1 Couples cAMP Signaling to a Distinct Pool of p42/44MAPK Regulating Excitability, Synaptic Plasticity, Learning, and Memory , 2003, Neuron.

[60]  Bernardo L Sabatini,et al.  Ca2+ signaling in dendritic spines , 2007, Current Opinion in Neurobiology.

[61]  J. Sweatt,et al.  NMDA Receptor Activation Increases Cyclic AMP in Area CA1 of the Hippocampus via Calcium/Calmodulin Stimulation of Adenylyl Cyclase , 1993, Journal of neurochemistry.

[62]  M. Kennedy,et al.  Regulation of the Neuron-specific Ras GTPase-activating Protein, synGAP, by Ca2+/Calmodulin-dependent Protein Kinase II* , 2004, Journal of Biological Chemistry.

[63]  T. Bartol,et al.  Monte Carlo simulation of miniature endplate current generation in the vertebrate neuromuscular junction. , 1991, Biophysical journal.

[64]  S. Nelson,et al.  Hebb and homeostasis in neuronal plasticity , 2000, Current Opinion in Neurobiology.

[65]  D. Ethell,et al.  Fas Ligand-Mediated Apoptosis in Degenerative Disorders of the Brain , 2003, Journal of Clinical Immunology.

[66]  Xiaobing Chen,et al.  Distribution of Postsynaptic Density (PSD)-95 and Ca2+/Calmodulin-Dependent Protein Kinase II at the PSD , 2003, The Journal of Neuroscience.

[67]  J. Ninomiya-Tsuji,et al.  Involvement of ASK1 in Ca2+‐induced p38 MAP kinase activation , 2004, EMBO reports.

[68]  U. Frey,et al.  Synaptic tagging: implications for late maintenance of hippocampal long-term potentiation , 1998, Trends in Neurosciences.

[69]  Michael W. Salter,et al.  Src kinases: a hub for NMDA receptor regulation , 2004, Nature Reviews Neuroscience.

[70]  Gary Lynch,et al.  Theta Stimulation Polymerizes Actin in Dendritic Spines of Hippocampus , 2005, The Journal of Neuroscience.

[71]  G. Banker,et al.  Neuronal Calcium Activates a Rap1 and B-Raf Signaling Pathway via the Cyclic Adenosine Monophosphate-dependent Protein Kinase* , 2000, The Journal of Biological Chemistry.

[72]  P. Greengard,et al.  Phosphodiesterase 1B Knock-Out Mice Exhibit Exaggerated Locomotor Hyperactivity and DARPP-32 Phosphorylation in Response to Dopamine Agonists and Display Impaired Spatial Learning , 2002, The Journal of Neuroscience.

[73]  R. Mains,et al.  Kalirin, a Multifunctional Rho Guanine Nucleotide Exchange Factor, Is Necessary for Maintenance of Hippocampal Pyramidal Neuron Dendrites and Dendritic Spines , 2003, The Journal of Neuroscience.

[74]  R. Klemke,et al.  Four Human Ras Homologs Differ in Their Abilities to Activate Raf-1, Induce Transformation, and Stimulate Cell Motility* , 1999, The Journal of Biological Chemistry.

[75]  L. Tsai,et al.  The p35/Cdk5 kinase is a neuron-specific Rac effector that inhibits Pak1 activity , 1998, Nature.

[76]  J. Macdonald,et al.  Abnormal Spine Morphology and Enhanced LTP in LIMK-1 Knockout Mice , 2002, Neuron.

[77]  Yehezkel Ben-Ari,et al.  The NMDA Receptor Is Coupled to the ERK Pathway by a Direct Interaction between NR2B and RasGRF1 , 2003, Neuron.

[78]  Gavin Rumbaugh,et al.  Phosphorylation of the AMPA Receptor GluR1 Subunit Is Required for Synaptic Plasticity and Retention of Spatial Memory , 2003, Cell.

[79]  Eric C. Griffith,et al.  Regulation of transcription factors by neuronal activity , 2002, Nature Reviews Neuroscience.

[80]  P. Tsichlis,et al.  AKT/PKB and other D3 phosphoinositide-regulated kinases: kinase activation by phosphoinositide-dependent phosphorylation. , 1999, Annual review of biochemistry.

[81]  P. Worley,et al.  Shank, a Novel Family of Postsynaptic Density Proteins that Binds to the NMDA Receptor/PSD-95/GKAP Complex and Cortactin , 1999, Neuron.

[82]  Yasuhiko Ohta,et al.  Hippocampal LTP Is Accompanied by Enhanced F-Actin Content within the Dendritic Spine that Is Essential for Late LTP Maintenance In Vivo , 2003, Neuron.

[83]  M. Behrens,et al.  Metabotropic Glutamate Receptor 1-Induced Upregulation of NMDA Receptor Current: Mediation through the Pyk2/Src-Family Kinase Pathway in Cortical Neurons , 2002, The Journal of Neuroscience.

[84]  John M. Lambert,et al.  Tiam1 mediates Ras activation of Rac by a PI(3)K-independent mechanism , 2002, Nature Cell Biology.

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

[86]  P. Katz,et al.  Biochemical networks in nervous systems: expanding neuronal information capacity beyond voltage signals , 2001, Trends in Neurosciences.

[87]  Michael E Greenberg,et al.  EphB Receptors Interact with NMDA Receptors and Regulate Excitatory Synapse Formation , 2000, Cell.

[88]  T. Sejnowski,et al.  Independent Sources of Quantal Variability at Single Glutamatergic Synapses , 2003, The Journal of Neuroscience.

[89]  S. Linse,et al.  Calcium binding to calmodulin and its globular domains. , 1991, The Journal of biological chemistry.

[90]  K. Martin,et al.  Synaptic tagging — who's it? , 2002, Nature Reviews Neuroscience.

[91]  R. Huganir,et al.  The Role of Synaptic GTPase-Activating Protein in Neuronal Development and Synaptic Plasticity , 2003, The Journal of Neuroscience.

[92]  M. Sheng,et al.  Targeted Protein Degradation and Synapse Remodeling by an Inducible Protein Kinase , 2003, Science.

[93]  M. Kennedy,et al.  SynGAP Regulates Spine Formation , 2004, The Journal of Neuroscience.

[94]  Suzanne Paradis,et al.  The Rac1-GEF Tiam1 Couples the NMDA Receptor to the Activity-Dependent Development of Dendritic Arbors and Spines , 2005, Neuron.

[95]  A. Means,et al.  Calmodulin: a prototypical calcium sensor. , 2000, Trends in cell biology.

[96]  M. Picciotto,et al.  Impaired Synaptic Plasticity and Learning in Mice Lacking β-Adducin, an Actin-Regulating Protein , 2005, The Journal of Neuroscience.

[97]  J. Hancock,et al.  Compartmentalization of Ras proteins. , 2001, Journal of cell science.

[98]  M. Sheng,et al.  PDZ domains and the organization of supramolecular complexes. , 2001, Annual review of neuroscience.

[99]  J. Hancock,et al.  Dominant-negative caveolin inhibits H-Ras function by disrupting cholesterol-rich plasma membrane domains , 1999, Nature Cell Biology.

[100]  Eric R Kandel,et al.  Local protein synthesis and its role in synapse-specific plasticity , 2000, Current Opinion in Neurobiology.

[101]  H. Markram,et al.  Regulation of Synaptic Efficacy by Coincidence of Postsynaptic APs and EPSPs , 1997, Science.

[102]  D. S. Cowen,et al.  Coupling of neuronal 5‐HT7 receptors to activation of extracellular‐regulated kinase through a protein kinase A‐independent pathway that can utilize Epac , 2003, Journal of neurochemistry.

[103]  J. Sanes,et al.  Can molecules explain long-term potentiation? , 1999, Nature Neuroscience.

[104]  Terrence J Sejnowski,et al.  Complexity of calcium signaling in synaptic spines. , 2002, BioEssays : news and reviews in molecular, cellular and developmental biology.

[105]  R. Malinow,et al.  Ras and Rap Control AMPA Receptor Trafficking during Synaptic Plasticity , 2002, Cell.

[106]  M. Dalva,et al.  Modulation of NMDA Receptor- Dependent Calcium Influx and Gene Expression Through EphB Receptors , 2001, Science.

[107]  Ravi Iyengar,et al.  Computational approaches for modeling regulatory cellular networks. , 2004, Trends in cell biology.

[108]  K. Hsu,et al.  Rap1-induced p38 Mitogen-activated Protein Kinase Activation Facilitates AMPA Receptor Trafficking via the GDI·Rab5 Complex , 2004, Journal of Biological Chemistry.

[109]  L. Luo,et al.  Intracellular signaling pathways that regulate dendritic spine morphogenesis , 2000, Hippocampus.

[110]  P. Stork.  Does Rap1 deserve a bad Rap? , 2003, Trends in biochemical sciences.

[111]  D. Storm,et al.  Synergistic activation of the type I adenylyl cyclase by Ca2+ and Gs-coupled receptors in vivo. , 1994, The Journal of biological chemistry.

[112]  C. Downes,et al.  Ca2+/Calmodulin-dependent Protein Kinase II Regulates Tiam1 by Reversible Protein Phosphorylation* , 1999, The Journal of Biological Chemistry.

[113]  H. Lübbert,et al.  Cloning and characterization of MUPP1, a novel PDZ domain protein , 1998, FEBS letters.

[114]  E. Lo,et al.  Developmentally regulated role for Ras‐GRFs in coupling NMDA glutamate receptors to Ras, Erk and CREB , 2004, The EMBO journal.

[115]  S. R. Datta,et al.  Cellular survival: a play in three Akts. , 1999, Genes & development.

[116]  Paul M Stemmer,et al.  Calmodulin is a limiting factor in the cell. , 2002, Trends in cardiovascular medicine.

[117]  K. Svoboda,et al.  The Life Cycle of Ca2+ Ions in Dendritic Spines , 2002, Neuron.

[118]  M. Constantine-Paton,et al.  The role of neural activity in synaptic development and its implications for adult brain function. , 1999, Advances in neurology.

[119]  J. Esteban,et al.  NMDA Receptor-Dependent Activation of the Small GTPase Rab5 Drives the Removal of Synaptic AMPA Receptors during Hippocampal LTD , 2005, Neuron.

[120]  R. Malenka,et al.  AMPA receptor trafficking and synaptic plasticity. , 2002, Annual review of neuroscience.

[121]  Mu-ming Poo,et al.  Neurotrophins as synaptic modulators , 2001, Nature Reviews Neuroscience.

[122]  D. Baltimore,et al.  Physiological functions for brain NF-κB , 2005, Trends in Neurosciences.

[123]  M. Sheng,et al.  The Shank family of scaffold proteins. , 2000, Journal of cell science.

[124]  R. Huganir,et al.  SynGAP: a Synaptic RasGAP that Associates with the PSD-95/SAP90 Protein Family , 1998, Neuron.

[125]  Richard G M Morris,et al.  Introduction. Long-term potentiation and structure of the issue. , 2003, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.