Recent evidence has suggested that alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionate/kainate (AMPA/KA) type glutamate receptors may contribute importantly to brain damage following hypoxic-ischemic insults in vivo. The proposed experiments will utilize the simplified model system of cortical cell cultures exposed to oxygen-glucose deprivation to address three aspects of this contribution: 1) the contribution of AMPA/KA receptor-mediated injury to overall hypoxic neuronal death, and the relationship between this AMPA/KA receptor-mediated injury and hypoxic NMDA receptor-mediated injury; 2) the role of AMPA/KA receptors in mediating the hypoxia-induced death specifically of a newly=discovered cortical neuronal subpopulation, that likely expresses large numbers of AMPA/KA receptor-gated Ca2+ channels, and hence may be especially vulnerable to AMPA/KA receptor-mediated injury; and 3) the effect of sublethal oxygen-glucose deprivation on the subsequent neuronal expression of GluR-2 mRNA and functional AMPA/KA receptor-gated Ca2+ channels. These studies should yield novel information about the way AMPA/KA receptors may mediate hypoxic neuronal death, which may prove valuable in guiding the developing of effective therapeutic strategies aimed at reducing this form of injury in disease settings such as stroke or cardiac arrest.
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