Mechanism of protection against ethanol sculpting of a striatal microcircuit

University Of Maryland Baltimore, Baltimore MD

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Abstract

? DESCRIPTION (provided by applicant): Alcoholism is a chronic, intractable disease characterized by heavy, uncontrollable drinking bouts occurring between periods of abstinence. Current treatments of alcoholism are limited in their ability to eliminate these drinking bouts. Ethanol alters the physiology of various cell types in a basal ganglia nucleus, the dorsolateral striatum (DLS). Chronic intermittent ethanol exposure specifically decreases inhibition onto the principal medium spiny projection neuron (MSN) in this region. The strongest inhibitory influence over MSN output comes from perisomatic innervations arising from the GABAergic fast-spiking interneuron (FSI). We find that this FSI-to-MSN (FSI-MSN) synapse is depressed in the presence of ethanol. Therefore, FSI-MSN depression may underlie the disinhibition of the DLS that occurs during ethanol exposure. Preventing ethanol-induced synaptic depression at this synapse may protect against compulsive drinking behaviors. A form of protection against a type of synaptic depression is known to occur in the marine mollusk Aplysia. A frequency-dependent stimulation protocol protects against the formation of synaptic depression through the activation of protein kinase C-alpha (PKC?), one of the Ca2+ sensitive forms of PKC. Remarkably, we are able to block ethanol-induced depression through a similar frequency-dependent PKC-activated mechanism. Thus, I hypothesize that activation of PKC? in FSIs protects the FSI-MSN synapse from the formation of ethanol-induced synaptic depression. I will test this hypothesis with two specific aims using both ex vivo and in vivo techniques. First, I will elucidate the mechanism underlying the frequency-dependent protection at this synapse using whole-cell patch-clamp electrophysiology and optogenetics. Then, I will demonstrate if frequency-dependent protection blocks ethanol-induced depression of the FSI-MSN synapse during in vivo ethanol consumption. I will test this prediction using in vivo optogenetics and a mouse drinking paradigm. Through these experiments I aim to identify a novel molecular target to offer an effective intervention for problem drinking, a major initiative stated by the National Institute for Alcohol Abuse and Alcoholism.