Striatal Mechanisms of Levodopa-Induced Dyskinesia

项目摘要 左旋多巴诱导的运动障碍（LID）通常在帕金森病的长期治疗期间发展， 大多数患者在治疗5-10年后仍会受到影响。不正常的不自主运动最终限制了 左旋多巴剂量，并且通常患者需要深部脑刺激（DBS）。LID的神经机制不是 完全理解，但主要的假设是左旋多巴触发输入核的异常活动， 基底神经节纹状体然而，即使在疾病的晚期，左旋多巴仍然具有 治疗和病理作用，促进正常运动和异常不自主运动。 这一临床观察使我们假设，在纹状体内，不同的神经元群体 与运动障碍对比左旋多巴的促运动（治疗）作用。我们的初步研究表明， 纹状体神经元的一部分在它们的活动中显示出与增加的正常运动或 运动障碍，很少有神经元与这两种反应相关。通过了解内在的和突触的 区分这两组纹状体神经元的特性，随后的药物开发可能能够 选择性靶向运动神经元，缓解帕金森病的运动症状，而不影响 运动障碍神经元和避免运动障碍。使用唤醒行为单一单元记录的组合， 光遗传学和LID小鼠模型中的离体切片记录，该提议旨在（1）表征 纹状体直接通路神经元对左旋多巴的反应，包括识别其放电与 运动障碍，（2）确定这些神经元是否引起运动障碍，以及（3）识别潜在的细胞 机制（内在兴奋性和/或兴奋性输入的改变）区分它们。测试 运动障碍相关的纹状体单位在运动障碍中的因果作用，我们将使用新的转基因工具，靶向 活动人群中的捕获（TRAP），允许捕获和随后操纵先前的 激活的神经元这些研究将提供第一个详细的观察左旋多巴是否触发治疗性 和运动障碍的影响，通过两个不同的纹状体效应人群，并开始解剖的基础 细胞和突触机制。 !

Project Summary Levodopa-induced dyskinesia (LID) commonly develops during long-term treatment of Parkinson's Disease, affecting most patients after 5-10 years of treatment. The abnormal involuntary movements eventually limit the levodopa dose, and often patients require deep brain stimulation (DBS). The neural mechanisms of LID are not fully understood, but the leading hypothesis is that levodopa triggers aberrant activity in the input nucleus of the basal ganglia, the striatum. Even in the advanced stages of disease, however, levodopa continues to have both therapeutic and pathological effects, promoting normal movement and abnormal involuntary movements. This clinical observation led us to hypothesize that within the striatum, distinct populations of neurons correlate with dyskinetic versus prokinetic (therapeutic) effects of levodopa. Our pilot studies indicate that a substantial fraction of striatal neurons show strong correlations in their activity with either increased normal movement, or dyskinesia, and few neurons correlate with both responses. By understanding the intrinsic and synaptic properties that distinguish these two groups of striatal neurons, subsequent drug development might be able to selectively target movement neurons, relieving motor symptoms of Parkinson's Disease, without affecting dyskinetic neurons and avoiding dyskinesia. Using a combination of awake-behaving single-unit recordings, optogenetics, and ex vivo slice recordings in a mouse model of LID, this proposal aims to (1) characterize striatal direct pathway neuronal responses to levodopa, including identifying units whose firing correlates with dyskinesia, (2) determine whether these neurons cause dyskinesia, and (3) identify the underlying cellular mechanisms (alterations in intrinsic excitability and/or excitatory inputs) that distinguish them. To test the causal role of dyskinesia-correlated striatal units in dyskinesia, we will use the novel transgenic tool, Targeted Recombination in Active Populations (TRAP), which allows capture and subsequent manipulation of previously activated neurons. These studies will provide the first detailed look at whether levodopa triggers therapeutic and dyskinetic effects through two different striatal effector populations, and begin to dissect the underlying cellular and synaptic mechanisms. !