This project investigates the possible involvement of the GABA/benzodiazepine/barbiturate receptor complex (now termed the GABAA receptor) in the pathophysiology of epilepsy. We propose that epileptogenesis may in some cases involve an aberration of normal plasticity mechanisms in which GABA receptors are altered at the level of subunit gene expression or at the level of protein functional regulation in response to some environmental stress. GABAA receptors and also excitatory amino acid receptors are to be compared in human focal epilepsy patients and normal and in an animal model of epilepsy in which rats are 'kindled' with GABA antagonist convulsant drugs. We have found that GABA receptors are lower than normal in midbrain of gerbils and mice with genetic susceptibility to generalized seizures. We have found a loss of GABA receptors in hippocampus and a structural reorganization of GABA receptors in dentate gyrus of human patients undergoing surgery for focal temporal lobe epilepsy. We have found in another project that GABA receptor properties and subunits are altered following chronic intermittent administration of ethanol to rats, producing repeated withdrawals, followed by a long-lasting hypersensitivity to seizures elicited by GABA antagonists. We propose that repeated over-activity of GABA synapses may produce an adaptive plastic response that could increase seizure susceptibility, i.e., a unified theory of epileptogenesis. Receptor density, distribution, and pharmacological properties will be studied by Northern blot analysis and radioligand binding autoradiography in sections from cortical and hippocampal brain tissue surgically removed from patients with partial complex seizures, and from chemically kindled rats compared to normal. Receptor function including pharmacological subtype characterization and second messenger/phosphorylation will be assessed by brain slice and membrane homogenate 36C1 flux assays, and by electrophysiological studies on GABA and EAA-elicited currents in Xenopus oocytes following injection of mRNA from brain tissue of human epilepsy patients and normal and chemically kindled rats. The proposed work in animals and human brain should further understanding of basic mechanisms and possible new therapies for the epilepsies.
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