Glutamatergic neurotransmitter systems are widely distributed in the mammalian CNS, and they are involved in excitatory synaptic transmission, synaptic plasticity, and in neural development. Glutamate receptors are also involved in neural injury from hypoxia-ischemia (stroke). This project will concentrate upon the AMPA subset of glutamate receptors and its role in hypoxic-ischemic neuronal injury. AMPA receptors mediate rapid, excitatory signalling between central neurons, and exhibit the property of rapid desensitization. This property of AMPA receptors is studied with patch-clamp electrophysiology in conjunction with pharmacological manipulation of AMPA desensitization, which has advanced significantly following the recent discovery in this laboratory of several drugs that specifically alter the desensitization properties of AMPA receptors. Concommitantly, AMPA receptors have emerged as important mediators of neuronal injury during experimental ischemia, producing great interest in understanding the modulatory factors (such as desensitization) for the purpose of targeting this receptor for therapeutic intervention in the treatment of stroke in an analogous fashion applied to the different sites on the NMDA receptor for the treatment of stroke and epilepsy or the GABA receptor for the treatment of epilepsy and anxiety disorders. The objectives of this proposal are to use patch-clamp electrophysiology in conjunction with receptor pharmacology and molecular biology in cell culture systems, cell lines expressing glutamate receptors, explant cultures of brain slices, and acutely prepared brain slices to identify regulatory mechanisms of AMPA receptor desensitization, and to determine how desensitization influences neuronal vulnerability to hypoxic-ischemic damage. Validation of the influence of these mechanisms upon hypoxic-ischemic neuronal damage will be examined in cultured cortical and hippocampal neurons, and hippocampal explant cultures subjected to oxygen-glucose deprivation ('in vitro ischemia'), as well as in rodents subjected to focal and global ischemia in order to expand these principles to more intact systems and live experimental animals. The long-term goal of this proposal is to enhance our understanding of the cellular mechanisms underlying the pathophysiology of stroke, and to expand and improve available means to treat patients who suffer from strokes.
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