Endogenous neurosteroid regulation of GABAARs.

University Of California Los Angeles, Los Angeles CA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Catamenial epilepsy manifests at specific stages of the ovarian cycle and the pathogenesis has been attributed to fluctuations in neurosteroid levels. Neuroactive steroids, such as progesterone and its metabolites, have been shown potentiate the effects of GABA at GABAA receptors (GABAARs) and act as anticonvulsants. The pharmacology of GABAARs is dependent upon receptor subunit composition. GABAAR kinetics are conferred by the receptor subunit composition. Specifically, neurosteroid modulation of GABAARs has been shown to be dependent upon the inclusion of the GABAAR . subunit. This subunit also mediates GABAergic tonic inhibition and regulation of this subunit may have profound results on excitability. Administration of exogenous neurosteroids and withdrawal from exogenous neurosteroid administration has been shown to regulate GABAAR subunit composition. The goal of this proposal is to investigate the role of fluctuating neurosteroid levels over the estrous cycle in the regulation of GABAAR subunits. We hypothesize that endogenous neurosteroids dynamically reorganize GABARs, leading to changes in GABAergic synaptic transmission, neuronal excitability, and seizure predisposition. [unreadable] [unreadable] [unreadable]