| Abstract |
Alcoholism is a costly disease that is responsible for a significant portion of the global disease burden, yet there is much is left to know about how this disease develops. Tolerance plays a critical role in predisposing an individual to alcohol abuse. Recently, the active zone of presynaptic neurons has been implicated as an ethanol effector. In this study, we examined the role that a presynaptic active zone protein, Dunc13, plays in the formation of tolerance to alcohol. Dunc13 is an ortholog of mammalian Unc13-1, and through the use of Drosophila as a model system, we show that genetic reduction of this protein creates ethanol resistance in naïve flies. This genetic reduction is also used as a tool to examine the transcriptome that results from alcohol exposure. mRNA samples were sequenced from haploinsufficient Dunc13 flies, as well as wildtype Canton-S flies. These sequences were used to identify genes that are differentially expressed between these two genotypes without exposure to ethanol and four hours after a sedating dose of ethanol. Naive and ethanol exposed haploinsufficient Dunc13 flies did not have any genes with significantly different levels of expression. This indicates Dunc13 flies are transcriptionally resistant to ethanol treatment. The genetic manipulation creates a neurophysiological state that does not have a differential response to rapid ethanol tolerance, highlighting the importance of this protein in the acquisition of tolerance. Further, the genes identified in this study contribute to the platform with which alcohol tolerance can be studied.
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