The striatal cholinergic interneurons in Parkinson's disease and treatment

项目摘要/摘要 帕金森病(PD)的多巴胺能治疗是最成功的基本治疗方法 解决神经退行性疾病中神经递质缺陷的方法。然而，它受到以下因素的限制 运动波动，包括在几年的治疗中发展起来的运动障碍。目前还不清楚是否 疾病进展或治疗是产生L多巴诱发的运动障碍(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 LID的主要贡献者。在帕金森病小鼠身上反复给药L-多巴会产生LID，这是 细胞外证据与纹状体胆碱能中间神经元(CHI)的高兴奋性相关 信号调节激酶(ERK)的激活和CHI对多巴胺的增强反应。此外， 通过阻止ERK激活或M受体，LID的表达部分减弱 对抗者。在6-OHDA损毁造成的帕金森病小鼠模型中，消融CHI显著减少盖子。 为了进一步定义CHI的作用，我们将利用一种新的方法来选择性地激活或抑制 使用转基因小鼠的由设计药物(DREADD)系统特异性激活的CHI Cre在CHI中的表达和腺病毒介导的DREADD向纹状体CHI的转移 我们将分别确定CHI在LID发育和表达中的作用。这样做的结果是 实验将表明根本不同的方法，要么作为预防 防止LID的发展或一旦LID表达已经有了症状控制 发展起来的。然后，我们将通过以下方法描述与LID相关的CHI多动的细胞机制 检测基因表达变化、形态改变和电生理特性。 多学科方法将为我们提供必要的洞察力和工具来设计治疗方法 接近盖子。

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.