The striatal cholinergic interneurons in Parkinson's disease and treatment

纹状体胆碱能中间神经元在帕金森病及其治疗中的作用

• 批准号: 9333674
• 负责人: Un Jung Kang
• 金额: $ 39.63万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9333674
• 关键词: Ablation; Address; Affect; Age of Onset; Anatomy; Animals; Attenuated; Basal Ganglia; Chronic; Clinical; Clozapine; Complement; Complex; Corpus striatum structure; Coupled; Data; Deafferentation procedure; Deep Brain Stimulation; Development; Disease; Disease Progression; Dopamine; Dopaminergic Agents; Drug Exposure; Dyskinetic syndrome; Electrophysiology (science); Exposure to; Extracellular Signal Regulated Kinases; Financial compensation; Future; G-Protein-Coupled Receptors; Gene Expression; Gene Expression Profile; Genes; Genetic Recombination; Genetic Transcription; Hyperactive behavior; Hypersensitivity; Individual; Interneurons; Ion Channel; L-DOPA induced dyskinesia; Laboratories; Lesion; Levodopa; Ligands; Light; Literature; LoxP-flanked allele; Measures; Methods; Mitogen-Activated Protein Kinases; Molecular; Morphology; Motor; Mus; Muscarinic Acetylcholine Receptor; Neurites; Neurodegenerative Disorders; Neurons; Neurotransmitters; Outcome; Oxides; Parkinson Disease; Parkinsonian Disorders; Pharmacology; Pharmacotherapy; Phase; Physiological; Physiological Processes; Physiology; Preparation; Process; Property; Prophylactic treatment; Publications; Regulator Genes; Replacement Therapy; Reporting; Role; Severity of illness; Signal Transduction; Slice; System; Systems Biology; Testing; Therapeutic; Time; Transgenic Mice; Viral; abnormal involuntary movement; adenovirus mediated delivery; cell type; cholinergic; clinically relevant; designer receptors exclusively activated by designer drugs; experimental study; functional outcomes; in vivo; insight; interdisciplinary approach; mouse model; novel; novel therapeutics; prevent; receptor; response; targeted treatment; tool; transcriptome; transmission process

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.

项目总结/文摘