Striatopallidal GABAergic Signaling in Mouse Models of Parkinson's Disease

描述(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。帕金森病的核心运动症状可归因于中脑多巴胺能神经元的退化和基底神经节神经元活动的改变。在帕金森病患者和灵长类帕金森病动物模型中，基底节球外段(GPE)的神经元以同步、高频的节律性爆发而出现尖峰。这种病理生理活动被认为是导致帕金森病患者运动迟缓、动作迟缓和僵硬的原因。在过去20年主导该领域的流行模型假设纹状体蛋白(CPU-GPE)GABA能抑制输入在多巴胺耗竭后升高到GPE。然而，这一猜想还没有在实验上得到证实。特别是，调控CPU-GPE突触传递的细胞和分子决定因素还没有完全了解。更重要的是，它们在疾病状态下的适应仍然完全没有被探索。在这个提议中，我们假设CPU-GPE在突触前和突触后的改变都是由于基底节回路中的多巴胺能去神经的结果，从而导致了疾病的运动症状。通过在帕金森病小鼠模型中融合电生理、药理学、转录和免疫细胞化学分析，该项目追求三个具体目标，以解决GPE中GABA能输入的基本机制。利用帕金森病小鼠模型，我们的目标是识别并最终协调纹状体苍白质突触中的特定分子变化。我们的目标是：1)研究纹状体苍白质突触的生理特性。2)研究GPE神经元表达的GABAA受体亚型。3)研究纹状体延髓传入与GPE神经元内源性电导之间的相互作用。 公共卫生相关性：这些研究的目的是纠正晚期帕金森病患者的大脑活动障碍。我们的目标的成功实现不仅可以为晚期帕金森病提供一种新的治疗方法，而且可以为药物治疗开辟新的途径。

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.