Presynaptic Plasticity in Ethanol Tolerance Circuitry

The first exposure to ethanol alters neuron function that manifests behaviorally with subsequent exposures. Tolerance development, a simple stimulus-response paradigm for plasticity, is ideal for identifying functionally relevant cellular and molecular plasticity substrates. In Drosophila, the mushroom body circuitry promotes multiple forms of ethanol plasticity including tolerance.Here, I show that ethanol physically changes presynapses in the mushroom bodies. Acute ethanol alters the expression of the presynaptic proteins Synapsin, Cdk5, and the Cav2.1 calcium channel (Cacophony) via the histone/protein deacetylase Sirt1 and the transcription factor Hr38. I found that acute ethanol increases presynapse size, scaling with ethanol dose. Increased synapse size is Sirt1 and Hr38-dependent, suggesting that it is part of a unified signaling pathway for synaptic remodeling by ethanol. Tolerance brain regions outside of the mushroom bodies are not known. I used a functional anatomical screen of sparsely expressed Gal4 strains driving Cacophony RNAi. I discovered three new sites for ethanol tolerance development, including the first demonstration of glutamatergic neurons in tolerance development. Further investigation of these glutamatergic tolerance neurons reveals that they are likely to be the DN1p clock neurons, demonstrating for the first time a role for the DN1p’s in tolerance. Together these data imply that ethanol has a widespread impact on the presynapses of the brain and further research is necessary to determine if and how these presynapses are involved in other ethanol behaviors