Striatopallidal GABAergic Signaling in Mouse Models of Parkinson's Disease

帕金森病小鼠模型中的纹状体苍白球 GABA 信号传导

• 批准号: 8271399
• 负责人: Savio Chan
• 金额: $ 31.8万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8271399
• 关键词: Address; Affinity; Aminobutyric Acids; Basal Ganglia; Bradykinesia; Brain; Corpus striatum structure; Data; Denervation; Disease; Disease model; Dopamine; Electron Microscopy; Fire - disasters; Frequencies; Modeling; Molecular; Motor; Neurodegenerative Disorders; Neurons; Parkinson Disease; Patients; Pattern; Pharmacological Treatment; Physiological; Primates; Property; Proteins; Signal Transduction; Staging; Symptoms; Synapses; base; dopaminergic neuron; gamma-Aminobutyric Acid; mouse model; novel; postsynaptic; presynaptic; public health relevance; receptor; response; transcriptomics; transmission process

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is the second most common neurodegenerative disease in the U.S. The core motor symptoms of PD are attributable to the degeneration of the mesencephalic dopaminergic neurons and alterations in the activity of neurons in the basal ganglia. In PD patients and in primate PD models, neurons in the external segment of the globus (GPe) of the basal ganglia spike in synchronous, high frequency rhythmic bursts. This pathophysiological activity is thought to be responsible for bradykinesia, akinesia, and rigidity in PD patients. The prevailing model that has dominated the field for the last two decades assumes an elevation in striatopallidal (CPu-GPe) GABAergic inhibitory input to the GPe following dopamine depletion. However, this conjecture has not been experimentally established. In particular the cellular and molecular determinants that regulate the transmission at the CPu-GPe synapse have not been fully understood. More importantly, their adaptations in disease state remain completely unexplored. In this proposal, we hypothesize that both pre- and post-synaptic alterations of the CPu-GPe occur as a result of dopaminergic denervation within the basal ganglia circuit, contributing to the motor symptoms of the disease. By blending electrophysiological, pharmacological, transcriptomic, and immunocytochemical analyses in mouse models of PD, this project pursues three specific aims addressing the basic mechanisms underlying GABAergic input to the GPe. Using mouse models of PD, we aim to identify and ultimately reconcile specific molecular changes in the striatopallidal synapse. Our aims are: 1) To characterize the physiological properties of the striatopallidal synapse. 2) To characterize the GABAA receptor subtypes expressed in GPe neurons. 3) To characterize the interaction between striatopallidal input and intrinsic conductances of GPe neurons. PUBLIC HEALTH RELEVANCE: These studies are aimed at correcting dysfunctional brain activity in late stage PD. The successful attainment of our aims could not only provide a novel therapy for late stage PD but open new avenues for pharmacological treatment.

描述（由申请人提供）：帕金森病（PD）是美国第二常见的神经退行性疾病。PD的核心运动症状可归因于中脑多巴胺能神经元的变性和基底神经节神经元活动的改变。在PD患者和灵长类PD模型中，基底节区球外节（GPe）的神经元以同步、高频、有节奏的爆发尖峰。这种病理生理活动被认为是PD患者运动迟缓、运动障碍和僵硬的原因。过去二十年来主导该领域的主流模型假设纹状体（CPu-GPe）对GPe的gaba能抑制输入在多巴胺消耗后升高。然而，这一猜想尚未得到实验证实。特别是调节CPu-GPe突触传递的细胞和分子决定因素尚未完全了解。更重要的是，它们在疾病状态下的适应性仍然是完全未知的。在这一建议中，我们假设CPu-GPe的突触前和突触后改变都是基底神经节回路内多巴胺能失神经支配的结果，从而导致疾病的运动症状。通过混合PD小鼠模型的电生理、药理学、转录组学和免疫细胞化学分析，该项目追求三个特定目标，解决gaba能输入GPe的基本机制。使用小鼠PD模型，我们的目标是确定并最终协调纹状体突触的特定分子变化。我们的目的是：1)表征纹状体突触的生理特性。2)研究GPe神经元中表达的GABAA受体亚型。3)研究纹状体输入与GPe神经元内在电导之间的相互作用。