The AMPA receptor-associated protein Shisa7 regulates hippocampal synaptic function and contextual memory

Glutamatergic synapses rely on AMPA receptors (AMPARs) for fast synaptic transmission and plasticity. AMPAR auxiliary proteins regulate receptor trafficking, and modulate receptor mobility and its biophysical properties. The AMPAR auxiliary protein Shisa7 (CKAMP59) has been shown to interact with AMPARs in artificial expression systems, but it is unknown whether Shisa7 has a functional role in glutamatergic synapses. We show that Shisa7 physically interacts with synaptic AMPARs in mouse hippocampus. Shisa7 gene deletion resulted in faster AMPAR currents in CA1 synapses, without affecting its synaptic expression. Shisa7 KO mice showed reduced initiation and maintenance of long-term potentiation of glutamatergic synapses. In line with this, Shisa7 KO mice showed a specific deficit in contextual fear memory, both short-term and long-term after conditioning, whereas auditory fear memory and anxiety-related behavior were normal. Thus, Shisa7 is a bona-fide AMPAR modulatory protein affecting channel kinetics of AMPARs, necessary for synaptic hippocampal plasticity, and memory recall.

[1]  D. Choquet,et al.  Regulation of AMPA receptor lateral movements , 2002, Nature.

[2]  R. Nicoll,et al.  TARP Subtypes Differentially and Dose-Dependently Control Synaptic AMPA Receptor Gating , 2007, Neuron.

[3]  T. Südhof,et al.  LTP Requires a Unique Postsynaptic SNARE Fusion Machinery , 2013, Neuron.

[4]  Michael B. Stadler,et al.  Encoding of conditioned fear in central amygdala inhibitory circuits , 2010, Nature.

[5]  R. Nicoll,et al.  The Expanding Social Network of Ionotropic Glutamate Receptors: TARPs and Other Transmembrane Auxiliary Subunits , 2011, Neuron.

[6]  Akio Sumioka.  Auxiliary subunits provide new insights into regulation of AMPA receptor trafficking. , 2013, Journal of biochemistry.

[7]  M. Fanselow,et al.  Modality-specific retrograde amnesia of fear. , 1992, Science.

[8]  Marco Y. Hein,et al.  The Perseus computational platform for comprehensive analysis of (prote)omics data , 2016, Nature Methods.

[9]  Xia Li,et al.  Inquiries into the Biological Significance of Transmembrane AMPA Receptor Regulatory Protein (TARP) γ-8 Through Investigations of TARP γ-8 Null Mice§. , 2015, CNS & neurological disorders drug targets.

[10]  M. Fanselow,et al.  Neurotoxic lesions of the dorsal hippocampus and Pavlovian fear conditioning in rats , 1997, Behavioural Brain Research.

[11]  R. Aebersold,et al.  A statistical model for identifying proteins by tandem mass spectrometry. , 2003, Analytical chemistry.

[12]  H. Adesnik,et al.  TARP gamma-8 controls hippocampal AMPA receptor number, distribution and synaptic plasticity. , 2005, Nature neuroscience.

[13]  N. Grishin,et al.  Unexpected diversity in Shisa-like proteins suggests the importance of their roles as transmembrane adaptors. , 2012, Cellular signalling.

[14]  M. Ehlers,et al.  Glutamate Receptor Dynamics in Dendritic Microdomains , 2008, Neuron.

[15]  Allan R. Jones,et al.  Genome-wide atlas of gene expression in the adult mouse brain , 2007, Nature.

[16]  A. Smit,et al.  Active heroin administration induces specific genomic responses in the nucleus accumbens shell , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[17]  Uwe Schulte,et al.  High-Resolution Proteomics Unravel Architecture and Molecular Diversity of Native AMPA Receptor Complexes , 2012, Neuron.

[18]  D. Bredt,et al.  AMPA receptor modulation by cornichon‐2 dictated by transmembrane AMPA receptor regulatory protein isoform , 2012, The European journal of neuroscience.

[19]  S. Tomita,et al.  The regulation of glutamate receptor trafficking and function by TARPs and other transmembrane auxiliary subunits , 2012, Current Opinion in Neurobiology.

[20]  T. Soderling,et al.  Regulatory mechanisms of AMPA receptors in synaptic plasticity , 2007, Nature Reviews Neuroscience.

[21]  Sandra Jurado.  The dendritic SNARE fusion machinery involved in AMPARs insertion during long-term potentiation , 2014, Front. Cell. Neurosci..

[22]  O. Thoumine,et al.  Activity-independent and subunit-specific recruitment of functional AMPA receptors at neurexin/neuroligin contacts , 2008, Proceedings of the National Academy of Sciences.

[23]  R. Nicoll,et al.  AMPA Receptor Trafficking at Excitatory Synapses , 2003, Neuron.

[24]  Connie R. Jimenez,et al.  On the beta-binomial model for analysis of spectral count data in label-free tandem mass spectrometry-based proteomics , 2010, Bioinform..

[25]  M. Farrant,et al.  Cornichons Modify Channel Properties of Recombinant and Glial AMPA Receptors , 2012, The Journal of Neuroscience.

[26]  Joseph E LeDoux,et al.  Rethinking the Fear Circuit: The Central Nucleus of the Amygdala Is Required for the Acquisition, Consolidation, and Expression of Pavlovian Fear Conditioning , 2006, The Journal of Neuroscience.

[27]  Mark von Zastrow,et al.  Role of ampa receptor endocytosis in synaptic plasticity , 2001, Nature Reviews Neuroscience.

[28]  H. Monyer,et al.  Auxiliary subunits of the CKAMP family differentially modulate AMPA receptor properties , 2015, eLife.

[29]  P. Castillo.  Presynaptic LTP and LTD of excitatory and inhibitory synapses. , 2012, Cold Spring Harbor perspectives in biology.

[30]  G. Buzsáki,et al.  Long-term potentiation induced by physiologically relevant stimulus patterns , 1987, Brain Research.

[31]  Peter Jonas,et al.  The Time Course of Signaling at Central Glutamatergic Synapses. , 2000, News in physiological sciences : an international journal of physiology produced jointly by the International Union of Physiological Sciences and the American Physiological Society.

[32]  L. Cantley,et al.  Recognition of Unique Carboxyl-Terminal Motifs by Distinct PDZ Domains , 1997, Science.

[33]  R. Weinberg,et al.  Shaping excitation at glutamatergic synapses , 1999, Trends in Neurosciences.

[34]  M. Mann,et al.  MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification , 2008, Nature Biotechnology.

[35]  R. Nicoll,et al.  Functional studies and distribution define a family of transmembrane AMPA receptor regulatory proteins , 2003, The Journal of cell biology.

[36]  R. Nicoll,et al.  Long-term potentiation--a decade of progress? , 1999, Science.

[37]  A. Smit,et al.  Morphine exposure and abstinence define specific stages of gene expression in the rat nucleus accumbens , 2004, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[38]  S. Tomita,et al.  Synaptic localization of neurotransmitter receptors: comparing mechanisms for AMPA and GABAA receptors. , 2015, Current opinion in pharmacology.

[39]  T. Lovenberg,et al.  Discovery and Characterization of AMPA Receptor Modulators Selective for TARP-γ8 , 2016, The Journal of Pharmacology and Experimental Therapeutics.

[40]  P. Jonas,et al.  Functional Proteomics Identify Cornichon Proteins as Auxiliary Subunits of AMPA Receptors , 2009, Science.

[41]  Richard L. Huganir,et al.  AMPARs and Synaptic Plasticity: The Last 25 Years , 2013, Neuron.

[42]  Hannah Monyer,et al.  CKAMP44: A Brain-Specific Protein Attenuating Short-Term Synaptic Plasticity in the Dentate Gyrus , 2010, Science.

[43]  Michael S Fanselow,et al.  Role of the Basolateral Amygdala in the Storage of Fear Memories across the Adult Lifetime of Rats , 2004, The Journal of Neuroscience.

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

[45]  A. Smit,et al.  Interaction proteomics reveals brain region-specific AMPA receptor complexes. , 2014, Journal of proteome research.

[46]  S. Tomita,et al.  CaMKII Phosphorylation of TARPγ-8 Is a Mediator of LTP and Learning and Memory , 2016, Neuron.

[47]  J. Coon,et al.  A proteomics search algorithm specifically designed for high-resolution tandem mass spectra. , 2013, Journal of proteome research.

[48]  D. Choquet.  Fast AMPAR trafficking for a high‐frequency synaptic transmission , 2010, The European journal of neuroscience.

[49]  B. Fakler,et al.  Cornichon2 Dictates the Time Course of Excitatory Transmission at Individual Hippocampal Synapses , 2014, Neuron.

[50]  R. Meredith,et al.  Ubiquitin ligase TRIM3 controls hippocampal plasticity and learning by regulating synaptic γ-actin levels , 2015, The Journal of cell biology.

[51]  Joseph E LeDoux,et al.  Lesions of the dorsal hippocampal formation interfere with background but not foreground contextual fear conditioning. , 1994, Learning & memory.

[52]  H. Mansvelder,et al.  C-Terminal Interactors of the AMPA Receptor Auxiliary Subunit Shisa9 , 2014, PloS one.

[53]  O. Stiedl,et al.  Impairment of conditioned contextual fear of C57BL/6J mice by intracerebral injections of the NMDA receptor antagonist APV , 2000, Behavioural Brain Research.

[54]  J. Yates,et al.  Differences in AMPA and kainate receptor interactomes facilitate identification of AMPA receptor auxiliary subunit GSG1L. , 2012, Cell reports.

[55]  Wade G Regehr,et al.  Short-term forms of presynaptic plasticity , 2011, Current Opinion in Neurobiology.

[56]  K. Roche,et al.  GSG1L suppresses AMPA receptor-mediated synaptic transmission and uniquely modulates AMPA receptor kinetics in hippocampal neurons , 2016, Nature Communications.

[57]  Charles D. Kopec,et al.  GluR1 Links Structural and Functional Plasticity at Excitatory Synapses , 2007, The Journal of Neuroscience.

[58]  R. Malinow,et al.  Activation of postsynaptically silent synapses during pairing-induced LTP in CA1 region of hippocampal slice , 1995, Nature.

[59]  H. Monyer,et al.  Coexpressed Auxiliary Subunits Exhibit Distinct Modulatory Profiles on AMPA Receptor Function , 2014, Neuron.

[60]  G. Buzsáki.  Theta rhythm of navigation: Link between path integration and landmark navigation, episodic and semantic memory , 2005, Hippocampus.

[61]  P. Rao-Ruiz,et al.  Retrieval-specific endocytosis of GluA2-AMPARs underlies adaptive reconsolidation of contextual fear , 2011, Nature Neuroscience.

[62]  D. Choquet,et al.  CaMKII Triggers the Diffusional Trapping of Surface AMPARs through Phosphorylation of Stargazin , 2010, Neuron.

[63]  A. Triller,et al.  The role of receptor diffusion in the organization of the postsynaptic membrane , 2003, Nature Reviews Neuroscience.

[64]  J. Trimmer,et al.  SynDIG1: An Activity-Regulated, AMPA- Receptor-Interacting Transmembrane Protein that Regulates Excitatory Synapse Development , 2010, Neuron.

[65]  S. Tomita,et al.  Porcupine Controls Hippocampal AMPAR Levels, Composition, and Synaptic Transmission. , 2016, Cell reports.

[66]  J. C. Lodder,et al.  Shisa6 traps AMPA receptors at postsynaptic sites and prevents their desensitization during synaptic activity , 2016, Nature Communications.

[67]  Daniel Choquet,et al.  Endocytic Trafficking and Recycling Maintain a Pool of Mobile Surface AMPA Receptors Required for Synaptic Potentiation , 2009, Neuron.

[68]  R. Huganir,et al.  The cell biology of synaptic plasticity: AMPA receptor trafficking. , 2007, Annual review of cell and developmental biology.

[69]  F. Gage,et al.  Neuronal medium that supports basic synaptic functions and activity of human neurons in vitro , 2015, Proceedings of the National Academy of Sciences.