The Role of Pre-Synaptic Munc 13-1 in Voluntary Ethanol Consumption and Tolerance
Wooden, Jessica I
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In the United States alone, approximately 18 million people suffer from alcohol use disorders. The role of the munc 13-1 pre-synaptic protein in alcohol-related behaviors has been little-studied, despite being a known site for ethanol binding. Munc 13-1 is an active zone protein that is vital for vesicle maturation at the synapse. Mice that are heterozygous for the gene regulating munc 13-1 produce synapses that, while structurally sound, show an approximate 50% decrease in this protein. Ethanol binds munc 13-1, decreasing its functional ability and likely antagonizing glutamatergic targets. Exposure to NMDA receptor antagonists has long been known to increase hippocampal neurogenesis, and it is likely that mice with inherently deficient NMDA stimulation would show the same pro-neurogenic outcomes. The current study aimed to perform a thorough behavioral analysis of mice heterozygous for munc 13-1. Few phenotypes have been identified in this specific type of mouse, and genetically engineered mice may express very different phenotypes from mutation to mutation. This project also endeavored to assess how loss of munc 13-1 affects voluntary binge and chronic alcohol consumption. Separately, munc 13-1 heterozygotes were evaluated for changes to acute functional tolerance following an injection of a standardized dose alcohol, using an accelerating rotarod as a measure of motor coordination. The last goal of the current project was to compare levels of doublecortin (DCX)-positive cells in the dentate gyrus between alcohol-exposed and alcohol-naïve mice, and also compare DCX levels across wildtype and heterozygous mice. Taken together, these results will give future researchers a better understanding of the role that pre-synaptic protein munc 13-1 plays in alcohol consumption and tolerance.