Dopamine transporter regulation of short-term plasticity in dopamine release

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Dopamine (DA) transmission within the striatum of the mammalian brain is critical for a wide range of processes, including reward information and action selection, and is dysregulated in disorders such as addiction and Parkinson's disease (PD). Striatal DA release transmission within the striatum is governed by multiple local processes including neuromodulatory inputs and intrinsic axonal mechanisms governing axonal excitability and neurotransmitter release probability. DA release probability within the striatum is not static but rather, it exhibits short-term plasticity which ranges from facilitation to depression. It has recently been shown that in addition to its canonical role in gating DA uptake, the DA transporter (DAT) regulates DA release and its dynamic plasticity. DAT inhibitors such as cocaine increase underlying DA release, and strongly modify short-term plasticity in DA release, by changing axonal calcium entry proposed to be due to changes to axon excitability. The DAT is therefore well placed to modulate DA function through several mechanisms. However, It is currently unclear how several properties of the DAT affect DA transmission and its short-term plasticity. In the proposed project, we will use fast scan cyclic voltammetry (FSCV) to detect DA in real-time in ex vivo striatal slices from mouse brain to explore DAT regulation of DA function more fully. We will assess the impact of DAT conformational state, post-translational modifications and trafficking, on striatal DA release and its short-term plasticity. We will also test directly the hypotheses that DATs modulate axonal activity, using state-of-the-art genetically encoded voltage sensors, and define interactions with other key modifiers of axonal activity including tonic GABA inhibition, in health and in a mouse model of Parkinson's. This project will provide fundamental new insights into how DATs on DA axons shape and govern dopamine function relevant to health and disease.