Effects of GABA Co-Release on Alcohol-Induced Synaptic Plasticity

Stanford University, Stanford CA

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Abstract

PROJECT SUMMARY Alcohol Use Disorder (AUD) is a chronically relapsing disorder for which few effective treatments exist. Excessive alcohol use causes a number of changes in the brain that promote increased alcohol use. One of the regions that has been shown to be affected by chronic alcohol is the dorsomedial striatum (DMS) which is involved in the control of goal-directed behaviors. Substantial evidence now shows that a history of alcohol exposure results in increased excitatory transmission in the DMS and that this increases alcohol intake. This brain region also receives inputs from the midbrain releasing the inhibitory neurotransmitter GABA which counteracts excitatory transmission. It has recently been shown that GABA released by this projection is synthesized by the enzyme ALDH1a1, and that acute alcohol decreases the amount of GABA released via this pathway. In this proposal, we will test the hypothesis that loss of this inhibitory input contributes to the pathology in AUD by causing excessive excitatory drive in the DMS. Because alterations in synaptic transmission cause long-term changes in the relative efficiency of communication between neurons, we will examine whether loss of inhibitory transmission results in (1) enhanced synaptic strengthening and (2) reduced synaptic weakening of excitatory transmission. Using 2-photon microscopy, slice electrophysiology, and fluorescent biosensors, we will mechanistically dissect the role of GABA release on synaptic plasticity. These experiments will advance our understanding of the neurobiology of alcohol in the DMS and may lead to better treatment strategies for AUD.