Presynaptic Site of Action of Neurosteroids

University Of New Mexico, Albuquerque NM

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Abstract

DESCRIPTION (provided by applicant): Neurosteroids have important roles in mental health-related disorders and these compounds have great potential for neuropsychopharmacological applications. Neurosteroids affect ligand-gated ion channels and metabotropic receptors by nongenomic mechanisms, but their mechanism of action is not completely understood. We have convincing preliminary evidence of a novel effect of the neurosteroids. We found that these compounds act at a presynaptic site to dramatically enhance glutamatergic paired-pulse facilitation, which is a model of short-term presynaptic plasticity. Additionally we observed an increase spontaneous miniature glutamatergic excitatory postsynaptic currents. We thus propose the following hypothesis: HYPOTHESIS: Neurosteroid actions in the CNS are due in part to enhancement of glutamate release in the hippocampus. To test this hypothesis we will address the following two specific aims: Specific Aim #1. Investigate the modulation of glutamate release by neurosteroids. We will use hippocampal slices and sharp-electrode electrophysiological techniques to study effect of two physiologically important neurosteroids, pregnenolone sulfate and dehydroapiandrosterone sulfate, on paired pulse facilitation. We will also examine effects of these compounds on spontaneous miniature glutamatergic excitatory postsynaptic currents. We will use hippocampal slices and whole-cell patch-clamp electrophysiological techniques for these studies. Specific Aim #2. Investigate the mechanisms by which neurosteroids modulate glutamate release. We will consider the role of presynaptic metabotropic receptors and ion channels in the modulation of glutamate release by neurosteroids. Specifically we will test a role of sigma receptors, voltage-gated calcium channels and potassium channels. The proposed studies will increase our understanding of the mechanism of action of these compounds in the brain.