Ischemic insults direct glutamate receptor subunit 2-lacking AMPA receptors to synaptic sites.
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.
Liu
Baosong
B
Division of Cellular and Molecular Biology, Toronto Western Research Institute, University Health Network, Toronto, Ontario, M5T 2S8, Canada.
Liao
Mingxia
M
Mielke
John G
JG
Ning
Ke
K
Chen
Yonghong
Y
Li
Lei
L
El-Hayek
Youssef H
YH
Gomez
Everlyne
E
Zukin
R Suzanne
RS
Fehlings
Michael G
MG
Wan
Qi
Q
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*
D018691:Excitatory Amino Acid Antagonists; D018091:Receptors, AMPA; D011493:Protein Kinase C; C104722:glutamate receptor ionotropic, AMPA 2