title: Activity-dependent synaptic GRIP1 accumulation drives synaptic scaling up in response to action potential blockade.
abstract: Synaptic scaling is a form of homeostatic plasticity that stabilizes neuronal firing in response to changes in synapse number and strength. Scaling up in response to action-potential blockade is accomplished through increased synaptic accumulation of GluA2-containing AMPA receptors (AMPAR), but the receptor trafficking steps that drive this process remain largely obscure. Here, we show that the AMPAR-binding protein glutamate receptor-interacting protein-1 (GRIP1) is essential for regulated synaptic AMPAR accumulation during scaling up. Synaptic abundance of GRIP1 was enhanced by activity deprivation, directly increasing synaptic GRIP1 abundance through overexpression increased the amplitude of AMPA miniature excitatory postsynaptic currents (mEPSCs), and shRNA-mediated GRIP1 knockdown prevented scaling up of AMPA mEPSCs. Furthermore, knockdown and replace experiments targeting either GRIP1 or GluA2 revealed that scaling up requires the interaction between GRIP1 and GluA2. Finally, GRIP1 synaptic accumulation during scaling up did not require GluA2 binding. Taken together, our data support a model in which activity-dependent trafficking of GRIP1 to synaptic sites drives the forward trafficking and enhanced synaptic accumulation of GluA2-containing AMPAR during synaptic scaling up.
authors.affiliation: Department of Biology and Center for Behavioral Genomics, Brandeis University, Waltham, MA 02454.
authors.forename: Melanie A
authors.initials: MA
authors.lastname: Gainey
authors.affiliation: Department of Biology and Center for Behavioral Genomics, Brandeis University, Waltham, MA 02454.
authors.forename: Vedakumar
authors.initials: V
authors.lastname: Tatavarty
authors.affiliation: Department of Biology and Center for Behavioral Genomics, Brandeis University, Waltham, MA 02454.
authors.forename: Marc
authors.initials: M
authors.lastname: Nahmani
authors.affiliation: Department of Biology and Center for Behavioral Genomics, Brandeis University, Waltham, MA 02454.
authors.forename: Heather
authors.initials: H
authors.lastname: Lin
authors.affiliation: Department of Biology and Center for Behavioral Genomics, Brandeis University, Waltham, MA 02454 turrigiano@brandeis.edu.
authors.forename: Gina G
authors.initials: GG
authors.lastname: Turrigiano
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D018613:Microscopy, Confocal; D016253:Microscopy, Immunoelectron; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D018408:Patch-Clamp Techniques; D011485:Protein Binding; D034622:RNA Interference; D020318:Rats, Long-Evans; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000378:metabolism / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D002352:Carrier Proteins; C491308:Grip1 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; D013779:Tetrodotoxin; C104722:glutamate receptor ionotropic, AMPA 2
keywords: AMPAR; GRIP1; GluA2; synaptic plasticity; synaptic scaling