The objective of this project is to investigate the hypothesis that an alteration in inhibitory synaptic transmission mediated by Gamma-aminobutyric acid (GABA) receptors may contribute to the pathophysiology of some types of epilepsy. Human brain tissue from temporal lobectomies performed on focal epilepsy patients and frozen autopsy material from epileptic patients, especially those with genetic factors, will be compared to non-epileptic tissue. In addition, three genetic animal models will be studied, the seizure-suceptible gerbil, the audiogenic seizure-sensitive mouse, and the tottering mouse mutant. The affinities and densities of receptors for GABA and associated modulatory drug receptors for benzodiazepines and for barbiturates/convulsants will be quantitatively determined by appropriate radioactive ligand binding in membrane homogenates of finely dissected brain regions or in tissue slices by autoradiography. Quisqualate/AMPA-sensitive glutamate receptor binding will be assayed in parallel. Preliminary results show a deficit in levels of benzodiazepine receptor binding sites in the substantia nigra and mid-brain periaqueductal gray regions of seizure-sensitive gerbils, suggesting an impairment of GABA-mediated inhibition in these midbrain regions. Since the substantia nigra GABAergic system has been implicated in controlling seizures of various kinds, a deficit in GABA receptors could contribute to seizure susceptibility. This finding will be further analyzed in gerbils as a function of seizure severity and ontogenic development of seizures. Midbrain areas, especially s. nigra, will be emphasized in the studies on other animal models and on human generalized seizure patients, where available. Findings by others of altered GABA nerve endings (gutamate decarboxylase immunoreactive) and GABA receptor binding in human and animal focal epilepsy suggest that studies on GABA receptors in human temporal lobe epilepsy also should be worthwhile. Parallel studies of the PI on the purification of the GABA receptor complex will likely lead to the early development of antibodies for radioimmune assay and immunocytochemical localization of these receptors, as well as development of tools of modern molecular biology for noninvasive analysis of gene expression for GABA receptors in human clinical disorders including the epilepsies. Mammals are needed for this study to produce any reasona- ble approximation to epilepsy in man. Animals at UCLA are cared for according to NIH Guidelines.
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