Dopamine transporter regulation of short-term plasticity in dopamine release

多巴胺转运蛋白对多巴胺释放短期可塑性的调节

• 批准号: 2607157
• 金额: --
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2607157
• 关键词: Dopamine; transporter; regulation; short; term

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.

哺乳动物大脑纹状体内的多巴胺（DA）传递对于包括奖励信息和动作选择在内的广泛过程至关重要，并且在成瘾和帕金森病（PD）等疾病中失调。纹状体内DA释放传递受多种局部过程支配，包括神经调节输入和支配轴突兴奋性和神经递质释放概率的内在轴突机制。纹状体内DA的释放概率不是静态的，而是表现出从易化到抑郁的短期可塑性。最近的研究表明，除了在门控DA摄取中的经典作用外，DA转运蛋白（DAT）还调节DA的释放及其动态可塑性。DAT抑制剂，如可卡因增加潜在的DA释放，并强烈修改DA释放的短期可塑性，通过改变轴突钙离子进入提出是由于轴突兴奋性的变化。因此，DAT通过几种机制很好地调节DA功能。然而，目前尚不清楚DAT的几个性质如何影响DA的传输及其短期可塑性。本研究拟利用快速扫描循环伏安法（FSCV）对离体小鼠纹状体脑片中的DA进行实时检测，以更全面地探讨DAT对DA功能的调控。我们将评估DAT构象状态，翻译后修饰和贩运，纹状体DA释放和短期可塑性的影响。我们还将直接测试DAT调节轴突活动的假设，使用最先进的遗传编码的电压传感器，并定义与轴突活动的其他关键修饰剂的相互作用，包括强直性GABA抑制，在健康和帕金森氏症的小鼠模型。该项目将为DA轴突上的DAT如何塑造和管理与健康和疾病相关的多巴胺功能提供基本的新见解。