Evaluating cell type-specific non-dopaminergics as a Parkinson's treatment paradigm

帕金森氏病（PD）是一种使人衰弱的神经退行性运动障碍，其特征在于神经元的丧失。 多巴胺能细胞主要治疗依赖于补充多巴胺（如左旋多巴），然而， 时间这些药物失去效力并导致失能左旋多巴诱导的运动障碍（LID）。这些 这些缺点表明PD不能单独通过多巴胺能途径来理解或治疗。在非- 多巴胺能机制，突触受体是操纵的主要候选者，但相关 迄今为止，实验尚未产生有希望的结果。这些干预措施缺乏细胞 特异性-纹状体与PD密切相关，含有不同的细胞类型，具有相反的行为特征。 功能.无法将药理学试剂靶向这些细胞类型中的一种， 对PD的认识和治疗存在差距。为了解决这一局限性，我们最近开发了DART（药物 Acutely Restricted by Tethering），这是一种基因编码的药物靶向技术， 以确定特定细胞类型上特定受体的行为作用。在本提案中，我们将应用细胞类型- 在小鼠模型中PD和LID的特异性突触受体干预。这项工作将提供前所未有的 PD和LID病理生理学的电路和分子见解。此外，它还可以提供一个路线图， 细胞类型特异性限制作为增加药物功效的潜在通用范例。

Parkinson’s disease (PD) is a debilitating neurodegenerative movement disorder, characterized by loss of dopaminergic cells. Primary treatments have relied on replenishing dopamine (e.g. levodopa), however, over time these drugs lose efficacy and lead to incapacitating levodopa induced dyskinesias (LID). These shortcomings suggest that PD cannot be understood or treated by dopaminergic pathways alone. Among non- dopaminergic mechanisms, synaptic receptors are prime candidates for manipulation, however relevant experiments have thus far not yielded promising results. These interventions have suffered from a lack of cellular specificity—the striatum, robustly implicated in PD, contains distinct cell types with opposing behavioral functionality. The inability to target pharmacological agents to just one of these cell types has produced a major gap in the understanding and treatment of PD. To address this limitation, we recently developed DART (Drugs Acutely Restricted by Tethering), a genetically encoded drug-targeting technology that offers the first opportunity to establish behavioral roles of a specific receptor on a defined cell type. In this proposal we will apply cell type- specific synaptic receptor interventions in PD and LID in mouse models. This work will provide unprecedented circuit and molecular insights into PD and LID pathophysiology. In addition, it may provide a roadmap for cell type-specific restriction as a potentially general paradigm for increasing drug efficacy.