GABA RECEPTOR ALTERATIONS DURING STATUS EPILEPTICUS

Children'S Hospital Of Philadelphia, Philadelphia PA

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Abstract

DESCRIPTION: (Verbatim from the Applicant's Abstract) Status epileptics (SE), defined as a single seizure lasting more than 30 min, or intermittent seizures lasting at least 30 min during which the patient does not regain consciousness, is a major medical emergency associate with significant morbidity and mortality. During SE, the function of many norm al neuronal processes is altered, resulting in the self-sustaining continuation of SE, and a progressive increase in drug intractability. Prolonged limbic seizures decrease GABAergic inhibition. The mechanisms underlying this decreased GABAergic efficacy are at least in part postsynaptic, and include reduced potency and efficacy of GABA, and altered transmembrane chloride gradients which decrease the driving force for IPSPs. This associate of loss of GABAergic inhibition wit SE has led us to formulate the CENTRAL HYPOTHESIS driving the experiments proposed in this application: inhibition progressively deteriorates during prolonged seizures, and this may be a primary contributor to the induction of self-sustaining SE activity, and may also explain the progressive development of drug intractability during protracted SE episodes. This central hypothesis is to be tested through experiments centered on 4 Specific Aims: Aim 1: Characterize alterations in GABAergic function in hippocampal neurons mediated by acute SE, including those mediated by SE-associated phosphorylation state changes. Aim 2: Characterize acute and chronic changes in GABA reversal potentials during and following SE, and examine the role SE-associated alterations in phosphorylation state of Cl channels and K-Cl cotransporters may play in altering E GABA. Aim 3: Examine alterations in expression patterns of GABAR subunit mRNAs and chloride homeostatic protein mRNAs in individual neurons during SE, and correlate these mRNA expression alteration with function of these various proteins assessed with patch clamp recordings in the same neurons. Aim 4: Examine the effects of NMDA receptor blockage, and GABAR blockade during SE on the phenomenon described in Aims 1-3. Understanding the mechanisms contributing to the induction of SE, and to the development of progressive drug intractability during prolonged SE are of obvious clinical significance, and may contribute to the development of new therapeutic strategies, which potentially could be effective in reducing the incidence of SE in at risk patients, and in treating prolonged SE more effectively once initiated.