The striatal cholinergic interneurons in Parkinson's disease and treatment

项目总结/摘要 帕金森病（PD）的多巴胺能治疗是合理治疗的最成功的例子 解决神经退行性疾病中神经递质缺乏的方法。然而，它受到以下限制： 运动波动，包括运动障碍，在几年的治疗中发展。目前尚不清楚是否 疾病进展或治疗是产生L-DOPA诱导的运动障碍（LID）的主要因素，但 临床和实验证据表明，发病年龄、疾病严重程度和慢性 多巴胺能药物暴露我们最近报道，胆碱能信号的升高可能是一种 主要贡献者LID。在帕金森病小鼠中重复给予L-DOPA产生LID， 与纹状体胆碱能中间神经元（ChI）的过度兴奋有关， 信号调节激酶（ERK）激活和ChI对多巴胺的反应增强。而且 LID的表达通过阻止ERK激活或毒蕈碱受体而部分减弱 拮抗剂在6-OHDA损伤产生的PD小鼠模型中，ChI消融显著降低了LID。 为了进一步确定ChI的作用，我们将利用一种新的方法，选择性地激活或抑制 使用转基因小鼠的设计者药物独家激活的设计者受体（DREADD）系统的ChI 在ChI中表达Cre和腺病毒介导的DREADD的floxed构建体向纹状体ChI的递送。 我们将分别确定ChI在LID发育和表达中的作用。这场 实验将表明从根本上不同的方法，无论是作为预防， 防止LID发展或用于LID表达的症状控制，一旦它已经 开发然后，我们将通过以下方式描述与LID相关的ChI过度活跃的细胞机制： 检测基因表达变化、形态学改变和电生理特性。 多学科的方法将为我们提供必要的见解和工具，以制定治疗 接近LID。

Project Summary/Abstract Dopaminergic therapy in Parkinson’s disease (PD) is the most successful example of rationale treatment approach addressing neurotransmitter deficit in neurodegenerative disorders. However, it is limited by motor fluctuations including dyskinesia that develops over several years of treatment. It is not clear if disease progression or treatment is the major factor in producing L-DOPA-induced dyskinesia (LID), but clinical and experimental evidences point to contributions of age of onset, disease severity, and chronic dopaminergic drug exposure. We have recently reported that elevated cholinergic signaling may be a major contributor to LID. Repeated L-DOPA administration in parkinsonian mice produces LID, which is associated with hyperexcitability of striatal cholinergic interneuron (ChI) evidenced by extracellular signal-regulated kinase (ERK) activation and enhanced response of ChI to dopamine. Moreover, the expression of LID was partially attenuated by preventing ERK activation or a muscarinic receptor antagonist. Ablation of ChI dramatically reduces LID in a mouse model of PD created by 6-OHDA lesion. To define the role of ChI further, we will utilize a novel method of selectively activating or suppressing ChI by Designer Receptor Exclusively Activated by Designer Drug (DREADD) system using transgenic mice expressing Cre in ChI and adenovirus-mediated delivery of floxed construct of DREADD to the striatal ChI. We will determine the role of ChI in LID development and expression separately. The outcome of this experiment would indicate fundamentally different approaches, either as a prophylaxis to prevent LID development or for symptomatic control of LID expression once it has already developed. We will then characterize cellular mechanisms of ChI hyperactivity associated with LID by examining gene expression changes, morphological alterations and electrophysiological properties. Multidisciplinary approaches will provide us necessary insights and tools to devise therapeutic approaches to LID.