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 receptordependent 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.

Direct-current electrical fields (EFs) promote nerve growth and axon regeneration. We report here that at physiological strengths, EFs guide the migration of neuronal stem/progenitor cells (NSPCs) toward the cathode. EF-directed NSPC migration requires activation of Nmethyl-D-aspartate receptors (NMDARs), which leads to an increased physical association of Rho GTPase Rac1-associated signals to the membrane NMDARs and the intracellular actin cytoskeleton. Thus, this study identifies the EF as a directional guidance cue in controlling NSPC migration and reveals a role of the NMDAR/Rac1/ actin signal transduction pathway in mediating EF-induced NSPC migration. These results suggest that as a safe physical approach in clinical application, EFs may be developed as a practical therapeutic strategy for brain repair by directing NSPC migration to the injured brain regions to replace cell loss.

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