The role of BRSK1, a PKC epsilon substrate, in behavioral and physiological responses to ethanol

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Project Summary/Abstract: Alcohol use disorder effects numerous people around the world and creates an enormous cost on society. The pharmacological treatments available are limited and modestly effective. One mechanism by which alcohol perturbs brain function is by altering synaptic transmission by altering the release probability of synaptic vesicles. The molecular mechanisms underlying this action are not known. Protein kinase C epsilon (PKCε) regulates both synaptic vesicle release and alcohol consumption in mice. Alcohol enhancement of inhibitory neurotransmission in the central amygdala (CeA), which is implicated in regulating alcohol consumption, is a process dependent on PKCε, and inhibition of PKCε in the CeA decreases alcohol consumption in mice. It is not known how PKCε regulates synaptic vesicle release. Brain serine/threonine kinase 1 (BRSK1) is phosphorylated by PKCε, colocalizes with pre-synaptic markers, and increases the release probability of synaptic vesicles. The objective of this project is to determine the role of BRSK1 in behavioral and physiological responses to alcohol and its relation to PKCε signaling. Based on preliminary evidence, the hypothesis is that BRSK1 via PKCε signaling mediates alcohol-induced GABA release in the CeA, limits sensitivity to ethanol intoxication, and promotes ethanol consumption and reward. This project will utilize several behavioral and pharmacological methods to determine the role of BRSK1 in behavioral responses to alcohol (Aim 1). The role of BRSK1 in alcohol-enhancement of inhibitory neurotransmission in primary neurons from the central amygdala will also be examined (Aim 2). The results of this project will increase understanding of the downstream signals that mediate PKCε regulation of alcohol related behaviors and alcohol’s enhancement of inhibitory transmission in neurons of the CeA. This project may also provide evidence for BRSK1 as a drug target for the development of novel treatments for alcohol use disorder.