Activity‐driven mobilization of post‐synaptic proteins

Synapses established during central nervous system development can be modified through synapse elimination and formation. These processes are, in part, activity dependent and require regulated trafficking of post‐synaptic components. Here, we investigate the activity‐driven remodeling of cultured rat hippocampal neurons at 14 days in vitro, focusing on the post‐synaptic proteins PSD‐95, Shank, neuroligin (NL)1 and actin. Using live imaging and photoconductive stimulation, we found that high‐frequency activity altered the trajectory, but not velocity, of PSD‐95‐GFP and Shank‐YFP clusters, whereas it reduced the speed and increased the number of NL1 clusters. Actin‐CFP reorganized into puncta following activity and ∼50% of new puncta colocalized with NL1 clusters. Actin reorganization was enhanced by the overexpression of NL1 and decreased by the expression of an NL1 mutant, NL1‐R473C. These results demonstrate activity‐dependent changes that may result in the formation of new post‐synaptic sites and suggest that NL1 modulates actin reorganization. The results also suggest that a common mechanism underlies both the developmental and activity‐dependent remodeling of excitatory synapses.

[1]  Y. Zhang,et al.  Altered synchrony and connectivity in neuronal networks expressing an autism-related mutation of neuroligin 3 , 2009, Neuroscience.

[2]  J. Hung,et al.  Astrocytic Ca2+ Waves Guide CNS Growth Cones to Remote Regions of Neuronal Activity , 2008, PloS one.

[3]  P. Dedon,et al.  Quantification of DNA damage products resulting from deamination, oxidation and reaction with products of lipid peroxidation by liquid chromatography isotope dilution tandem mass spectrometry , 2008, Nature Protocols.

[4]  M. Frerking,et al.  Spine Expansion and Stabilization Associated with Long-Term Potentiation , 2008, The Journal of Neuroscience.

[5]  Y. Goda,et al.  Actin in action: the interplay between the actin cytoskeleton and synaptic efficacy , 2008, Nature Reviews Neuroscience.

[6]  R. Dominguez,et al.  Structural basis for the recruitment of profilin–actin complexes during filament elongation by Ena/VASP , 2007, The EMBO journal.

[7]  P. Scheiffele,et al.  Neuroligin‐3 is a neuronal adhesion protein at GABAergic and glutamatergic synapses , 2007, The European journal of neuroscience.

[8]  K. Mori,et al.  Interaction between Telencephalin and ERM Family Proteins Mediates Dendritic Filopodia Formation , 2007, The Journal of Neuroscience.

[9]  T. Südhof,et al.  Activity-Dependent Validation of Excitatory versus Inhibitory Synapses by Neuroligin-1 versus Neuroligin-2 , 2007, Neuron.

[10]  Nicole Caspers,et al.  A thermodynamic ligand binding study of the third PDZ domain (PDZ3) from the mammalian neuronal protein PSD-95. , 2007, Biochemistry.

[11]  Gong Chen,et al.  Molecular reconstitution of functional GABAergic synapses with expression of neuroligin-2 and GABAA receptors , 2007, Molecular and Cellular Neuroscience.

[12]  L. Zeng,et al.  Hippocampal seizures cause depolymerization of filamentous actin in neurons independent of acute morphological changes , 2007, Brain Research.

[13]  S. Ishiura,et al.  Neuroligins 3 and 4X interact with syntrophin-gamma2, and the interactions are affected by autism-related mutations. , 2007, Biochemical and biophysical research communications.

[14]  Tsutomu Hashikawa,et al.  Retrograde modulation of presynaptic release probability through signaling mediated by PSD-95–neuroligin , 2007, Nature Neuroscience.

[15]  Y. Hata,et al.  Synaptic scaffolding molecule (S‐SCAM) membrane‐associated guanylate kinase with inverted organization (MAGI)‐2 is associated with cell adhesion molecules at inhibitory synapses in rat hippocampal neurons , 2007, Journal of neurochemistry.

[16]  Roberto Araya,et al.  Dendritic spines linearize the summation of excitatory potentials , 2006, Proceedings of the National Academy of Sciences.

[17]  A. McAllister,et al.  Formation of Presynaptic Terminals at Predefined Sites along Axons , 2006, The Journal of Neuroscience.

[18]  Borries Demeler,et al.  Gene selection, alternative splicing, and post-translational processing regulate neuroligin selectivity for beta-neurexins. , 2006, Biochemistry.

[19]  A. McAllister,et al.  Immunocytochemistry and quantification of protein colocalization in cultured neurons , 2006, Nature Protocols.

[20]  Thomas C. Südhof,et al.  Neuroligins Determine Synapse Maturation and Function , 2006, Neuron.

[21]  Xiang Li,et al.  Solution structure of GOPC PDZ domain and its interaction with the C‐terminal motif of neuroligin , 2006, Protein science : a publication of the Protein Society.

[22]  Shigeo Okabe,et al.  Differential Control of Postsynaptic Density Scaffolds via Actin-Dependent and -Independent Mechanisms , 2006, The Journal of Neuroscience.

[23]  Nelson Spruston,et al.  Distance-Dependent Differences in Synapse Number and AMPA Receptor Expression in Hippocampal CA1 Pyramidal Neurons , 2006, Neuron.

[24]  A. Craig,et al.  Structure Function and Splice Site Analysis of the Synaptogenic Activity of the Neurexin-1β LNS Domain , 2006, The Journal of Neuroscience.

[25]  A. El-Husseini,et al.  A Preformed Complex of Postsynaptic Proteins Is Involved in Excitatory Synapse Development , 2006, Neuron.

[26]  C. Altier,et al.  The Arg473Cys‐neuroligin‐1 mutation modulates NMDA mediated synaptic transmission and receptor distribution in hippocampal neurons , 2005, FEBS letters.

[27]  Y. Goda,et al.  The actin cytoskeleton: integrating form and function at the synapse. , 2005, Annual review of neuroscience.

[28]  A. Dunaevsky,et al.  Dendritic spine morphogenesis and plasticity. , 2005, Journal of neurobiology.

[29]  C. Marshall Comment on "Abrupt and Gradual Extinction Among Late Permian Land Vertebrates in the Karoo Basin, South Africa" , 2005, Science.

[30]  J. Meldolesi,et al.  Key Role of the Postsynaptic Density Scaffold Proteins Shank and Homer in the Functional Architecture of Ca2+ Homeostasis at Dendritic Spines in Hippocampal Neurons , 2005, The Journal of Neuroscience.

[31]  O. Prange,et al.  Neuroligins Mediate Excitatory and Inhibitory Synapse Formation , 2005, Journal of Biological Chemistry.

[32]  Lu Chen,et al.  Postsynaptic assembly induced by neurexin-neuroligin interaction and neurotransmitter , 2005, Proceedings of the National Academy of Sciences of the United States of America.

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

[34]  P. Scheiffele,et al.  Control of Excitatory and Inhibitory Synapse Formation by Neuroligins , 2005, Science.

[35]  H Sebastian Seung,et al.  Light-directed electrical stimulation of neurons cultured on silicon wafers. , 2005, Journal of neurophysiology.

[36]  Ann Marie Craig,et al.  Neurexins Induce Differentiation of GABA and Glutamate Postsynaptic Specializations via Neuroligins , 2004, Cell.

[37]  P. Scheiffele,et al.  Disorder-associated mutations lead to functional inactivation of neuroligins. , 2004, Human molecular genetics.

[38]  Igor Tsigelny,et al.  The Arg451Cys-Neuroligin-3 Mutation Associated with Autism Reveals a Defect in Protein Processing , 2004, The Journal of Neuroscience.

[39]  Thomas Bourgeron,et al.  Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism , 2003, Nature Genetics.

[40]  Y. Tano,et al.  Synaptic Targeting of PSD-Zip45 (Homer 1c) and Its Involvement in the Synaptic Accumulation of F-actin* , 2003, The Journal of Biological Chemistry.

[41]  E. Feldman,et al.  Signaling mechanisms that regulate actin‐based motility processes in the nervous system , 2002, Journal of neurochemistry.

[42]  Pascal Jourdain,et al.  LTP, memory and structural plasticity. , 2002, Current molecular medicine.

[43]  S. Narumiya,et al.  Multiple spatiotemporal modes of actin reorganization by NMDA receptors and voltage-gated Ca2+ channels , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[44]  T. Südhof,et al.  CASK Participates in Alternative Tripartite Complexes in which Mint 1 Competes for Binding with Caskin 1, a Novel CASK-Binding Protein , 2002, The Journal of Neuroscience.

[45]  Michael J. Sailor,et al.  Remodeling of Synaptic Actin Induced by Photoconductive Stimulation , 2001, Cell.

[46]  K. Frei,et al.  Identification of a novel neuroligin in humans which binds to PSD-95 and has a widespread expression. , 2001, The Biochemical journal.

[47]  Y. Goda,et al.  Actin-Dependent Regulation of Neurotransmitter Release at Central Synapses , 2000, Neuron.

[48]  R. Fetter,et al.  Neuroligin Expressed in Nonneuronal Cells Triggers Presynaptic Development in Contacting Axons , 2000, Cell.

[49]  T. Südhof,et al.  Neuroligin 1 is a postsynaptic cell-adhesion molecule of excitatory synapses. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[50]  A. Craig,et al.  Role of Actin in Anchoring Postsynaptic Receptors in Cultured Hippocampal Neurons: Differential Attachment of NMDA versus AMPA Receptors , 1998, The Journal of Neuroscience.

[51]  T. Südhof,et al.  Binding of neuroligins to PSD-95. , 1997, Science.

[52]  T. Südhof,et al.  Structures, Alternative Splicing, and Neurexin Binding of Multiple Neuroligins (*) , 1996, The Journal of Biological Chemistry.

[53]  P. Focia,et al.  Structural basis for synaptic adhesion mediated by neuroligin-neurexin interactions , 2008, Nature Structural &Molecular Biology.

[54]  Y. Goda,et al.  Photoconductive stimulation of neurons cultured on silicon wafers , 2006, Nature Protocols.

[55]  A. Craig,et al.  Structure function and splice site analysis of the synaptogenic activity of the neurexin-1 beta LNS domain. , 2006, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[56]  E. Kandel,et al.  Structural changes accompanying memory storage. , 1993, Annual review of physiology.