Ischemic insults direct glutamate receptor subunit 2-lacking AMPA receptors to synaptic sites

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

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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.

Original languageEnglish (US)
Pages (from-to)5309-5319
Number of pages11
JournalJournal of Neuroscience
Volume26
Issue number20
DOIs
StatePublished - Sep 8 2006

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Keywords

  • AMPA receptors
  • GluR2 subunit
  • Ischemia
  • Neuronal death
  • Receptor trafficking
  • Synapse

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Liu, B., Liao, M., Mielke, J. G., Ning, K., Chen, Y., Li, L., El-Hayek, Y. H., Gomez, E., Zukin, R. S., Fehlings, M. G., & Wan, Q. (2006). Ischemic insults direct glutamate receptor subunit 2-lacking AMPA receptors to synaptic sites. Journal of Neuroscience, 26(20), 5309-5319. https://doi.org/10.1523/JNEUROSCI.0567-06.2006