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The Journal of Neuroscience, May 17, 2006, 26(20):5309-5319; doi:10.1523/JNEUROSCI.0567-06.2006

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Cellular/Molecular
Ischemic Insults Direct Glutamate Receptor Subunit 2-Lacking AMPA Receptors to Synaptic Sites

Baosong Liu,^1,2,3 Mingxia Liao,^1,2,3 John G. Mielke,^1,2,3 Ke Ning,^1,2,3 Yonghong Chen,^1,2,3 Lei Li,^1,2,3 Youssef H. El-Hayek,^1,2,3 Everlyne Gomez,^1,2,3 R. Suzanne Zukin,⁵ Michael G. Fehlings,^1,3,4 and Qi Wan^1,2,3

¹Division of Cellular and Molecular Biology, Toronto Western Research Institute, University Health Network, Departments of ²Physiology and ³Surgery, and ⁴Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada M5T 2S8, and ⁵Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461

Correspondence should be addressed to either of the following: Dr. R. Suzanne Zukin, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Room 607 Kennedy, Bronx, NY 10461, Email: zukin{at}aecom.yu.edu or Dr. Qi Wan, Toronto Western Research Institute, University of Toronto, 399 Bathurst Street, McLaughlin Pavilion 14-409, Toronto, Ontario, Canada M5T 2S8, qi.wan{at}utoronto.ca

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.

Key words: ischemia; neuronal death; AMPA receptors; GluR2 subunit; synapse; receptor trafficking

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Received Aug. 22, 2004; revised April 9, 2006; accepted April 9, 2006.

Correspondence should be addressed to either of the following: Dr. R. Suzanne Zukin, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Room 607 Kennedy, Bronx, NY 10461, Email: zukin{at}aecom.yu.edu or Dr. Qi Wan, Toronto Western Research Institute, University of Toronto, 399 Bathurst Street, McLaughlin Pavilion 14-409, Toronto, Ontario, Canada M5T 2S8, qi.wan{at}utoronto.ca

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