Neurosteroid Regulation of Seizures

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DESCRIPTION (provided by applicant): Temporal lobe epilepsy (TLE) is a common form of medically refractory epilepsy characterized by recurrent unprovoked seizures involving the limbic structures, which often requires surgery. Multiple pathophysiological mechanisms have been proposed to explain seizure occurrence in TLE; among these is an altered GABAA receptor-mediated inhibition of dentate granule cells (DGCs). We demonstrated that GABAA receptors on DGCs of epileptic rats were far less sensitive to neurosteroid modulations than those on DGCs of control animals. Ongoing studies suggest that in DGCs of epileptic animals, there is reduced neurosteroid sensitivity of synaptic inhibition associated with the aberrant targeting of the a4 subunit to extrasynaptic, perisynaptic, and synaptic membrane. Furthermore, there is loss of neurosteroid sensitivity of tonic inhibition associated with diminished trafficking of the d subunit to the surface membrane as well as increased surface expression of the ? 2 in the hippocampi of epileptic rats. These studies suggest the hypotheses that in epileptic animals, there is breakdown of activity filtering function of DGCs during periods of diminished neurosteroid synthesis and seizures occur. We also propose that diminished neurosteroid sensitivity of tonic and synaptic inhibition on DGCs is because the d subunit is retained in intracellular compartment and d subunit-containing receptors are replaced by ?2 subunit-containing receptors. We propose to test the predictions of our hypotheses by accomplishing four specific aims: the first aim is to characterize the impact of diminished neurosteroid sensitivity of GABAA receptors on seizure susceptibility and granule cell excitability; the second aim will be to characterize neurosteroid sensitivity and ?2, d, a4, and a5 subunit-specific properties of tonic GABAergic inhibition of DGCs; and the third aim will be to determine the time course of altered trafficking, assembly, and targeting of ? 2,d, a4, and a5 subunits of GABAA receptors during the latent period and after the onset of recurrent seizures. Experiments in the fourth aim will characterize the effect of increased neuronal activity and agonist exposure on d subunit trafficking, endocytosis, and insertion rates. These studies investigate a novel mechanism of seizure precipitation in epileptic animals related to decline in endogenous neurosteroid levels and define a novel GABAA receptor as target for epilepsy therapy. PUBLIC HEALTH RELEVANCE These studies seek to understand the mechanisms underlying a common form of epilepsy. They also seek to understand how seizures might be precipitated in patients with epilepsy. These studies will seek a new target for developing drugs for the treatment of epilepsy.