The role of striatal cholinergic interneurons in Parkinson’s disease

纹状体胆碱能中间神经元在帕金森病中的作用

• 批准号: 9147020
• 负责人: Un Jung Kang
• 金额: $ 48.83万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9147020
• 关键词: Ablation; Acute; Address; Affect; Age of Onset; Animals; Attenuated; Basal Ganglia; Characteristics; Chronic; Clinical; Clozapine; Complex; Corpus striatum structure; Coupled; Development; Disease; Disease Progression; Dopamine; Dopamine D1 Receptor; Dopaminergic Agents; Drug Exposure; Dyskinetic syndrome; Electrophysiology (science); Exposure to; Financial compensation; Functional disorder; G-Protein-Coupled Receptors; Genetic Recombination; Glutamates; Health; Hyperactive behavior; Hypersensitivity; Interneurons; L-DOPA induced dyskinesia; Lesion; Letters; Levodopa; Ligands; Literature; LoxP-flanked allele; Measures; Methods; Mitogen-Activated Protein Kinases; Modeling; Molecular; Motor; Mus; Muscarinic Acetylcholine Receptor; Neurodegenerative Disorders; Neurons; Neurotransmitters; Output; Oxides; Parkinson Disease; Parkinsonian Disorders; Pathway interactions; Phase; Population; Primates; Property; Replacement Therapy; Reporting; Rodent; Role; Severity of illness; Signal Transduction; Slice; System; Testing; Time; Transgenic Mice; Viral; abnormal involuntary movement; adenovirus mediated delivery; base; cell type; cholinergic; designer receptors exclusively activated by designer drugs; effective therapy; gene therapy; in vivo; mouse model; neuronal circuitry; neurotransmission; novel; novel therapeutics; patch clamp; prevent; response; selective expression; targeted treatment; therapeutic target

 DESCRIPTION (provided by applicant): 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. We will characterize cellular mechanisms of ChI hyperactivity associated with LID. Finally, we will examine the effect of ChI on the excitability of the medium spiny neuron that is the major striatal output neuron.

 描述（由申请方提供）：帕金森病（PD）的多巴胺能治疗是解决神经退行性疾病中神经递质缺陷的合理治疗方法的最成功示例。然而，它受到运动波动的限制，包括在几年的治疗中发展的运动障碍。目前尚不清楚疾病进展或 治疗是产生L-DOPA诱导的运动障碍（LID）的主要因素，但临床和实验证据指出了发病年龄、疾病严重程度和慢性多巴胺能药物暴露的作用。我们最近报道，胆碱能信号的升高可能是LID的主要贡献者。在帕金森病小鼠中重复给予L-DOPA产生LID，其与纹状体胆碱能中间神经元（ChI）的过度兴奋有关， 通过细胞外信号调节激酶（ERK）激活和ChI对多巴胺的增强反应。此外，通过阻止ERK激活或毒蕈碱受体拮抗剂，LID的表达部分减弱。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ChI的设计师受体独家激活的设计师药物（DREADD）系统使用转基因小鼠表达Cre在ChI和腺病毒介导的交付的floxed构建DREADD纹状体ChI。我们将分别确定ChI在LID发育和表达中的作用。我们将描述与LID相关的ChI过度活跃的细胞机制。最后，我们将研究的影响，ChI的兴奋性的中型多刺神经元，是主要的纹状体输出神经元。