title: Ischemic insults direct glutamate receptor subunit 2-lacking AMPA receptors to synaptic sites.
abstract: Regulated AMPA receptor (AMPAR) trafficking at excitatory synapses is a mechanism critical to activity-dependent alterations in synaptic efficacy. The role of regulated AMPAR trafficking in insult-induced synaptic remodeling and/or cell death is, however, as yet unclear. Here we show that brief oxygen-glucose deprivation (OGD), an in vitro model of brain ischemia, promotes redistribution of AMPARs at synapses of hippocampal neurons, leading to a switch in AMPAR subunit composition. Ischemic insults promote internalization of glutamate receptor subunit 2 (GluR2)-containing AMPARs from synaptic sites via clathrin-dependent endocytosis and facilitate delivery of GluR2-lacking AMPARs to synaptic sites via soluble N-ethylmaleimide-sensitive factor attachment protein receptor-dependent exocytosis, evident at early times after insult. The OGD-induced switch in receptor subunit composition requires PKC activation, dissociation of GluR2 from AMPA receptor-binding protein, and association with protein interacting with C kinase-1. We further show that AMPARs at synapses of insulted neurons exhibit functional properties of GluR2-lacking AMPARs. AMPAR-mediated miniature EPSCs exhibit increased amplitudes and enhanced sensitivity to subunit-specific blockers of GluR2-lacking AMPARs, evident at 24 h after ischemia. The OGD-induced alterations in synaptic AMPA currents require clathrin-mediated receptor endocytosis and PKC activation. Thus, ischemic insults promote targeting of GluR2-lacking AMPARs to synapses of hippocampal neurons, mechanisms that may be relevant to ischemia-induced synaptic remodeling and/or neuronal death.
authors.affiliation: Division of Cellular and Molecular Biology, Toronto Western Research Institute, University Health Network, Toronto, Ontario, M5T 2S8, Canada.
authors.forename: Baosong
authors.initials: B
authors.lastname: Liu
authors.forename: Mingxia
authors.initials: M
authors.lastname: Liao
authors.forename: John G
authors.initials: JG
authors.lastname: Mielke
authors.forename: Ke
authors.initials: K
authors.lastname: Ning
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Chen
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Youssef H
authors.initials: YH
authors.lastname: El-Hayek
authors.forename: Everlyne
authors.initials: E
authors.lastname: Gomez
authors.forename: R Suzanne
authors.initials: RS
authors.lastname: Zukin
authors.forename: Michael G
authors.initials: MG
authors.lastname: Fehlings
authors.forename: Qi
authors.initials: Q
authors.lastname: Wan
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D022163:Clathrin-Coated Vesicles / Q000378:metabolism; D004195:Disease Models, Animal; D004705:Endocytosis / Q000502:physiology; D004789:Enzyme Activation / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005089:Exocytosis / Q000502:physiology; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism* / Q000503:physiopathology; D009410:Nerve Degeneration / Q000378:metabolism / Q000503:physiopathology; D009473:Neuronal Plasticity / Q000502:physiology; D011493:Protein Kinase C / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D018091:Receptors, AMPA; D011493:Protein Kinase C; C104722:glutamate receptor ionotropic, AMPA 2