Intrinsic and synaptic determinants of activity in GPe neurons in PD models

PD 模型中 GPe 神经元活性的内在和突触决定因素

• 批准号: 8544579
• 负责人: DALTON JAMES SURMEIER
• 金额: $ 11.59万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8544579
• 关键词: Address; Animal Model; Basal Ganglia; Behavior; Bradykinesia; Brain; Brain region; Cell Nucleus; Cessation of life; Coupling; Deep Brain Stimulation; Development; Disease; Disease model; Dopamine; Down-Regulation; Economics; Ensure; Equilibrium; Frequencies; Functional disorder; Globus Pallidus; Glutamates; Grant; Human; Ion Channel; Laboratories; Lesion; Link; Modeling; Molecular; Monkeys; Motor; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pathology; Patients; Pattern; Periodicity; Pharmacological Treatment; Primates; Property; Rodent; Rodent Model; Role; Signal Transduction; Staging; Structure of subthalamic nucleus; Substantia nigra structure; Symptoms; Synapses; Testing; Theoretical Studies; Therapeutic; Translations; Tremor; Viral; Work; dopaminergic neuron; gene therapy; insight; novel; novel therapeutics; pars compacta; restoration; skills

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 two key nuclei of the basal ganglia - the external segment of the globus (GPe) and the subthalamic nucleus (STN) - spike in synchronous, high frequency rhythmic bursts.This pathophysiological activity is thought to be responsible for bradykinesia, akinesia and rigidity in PD patients.Theoretical studies suggest that autonomous pacemaking in GPe neurons counter-balances the natural tendency of the reciprocally connected, STN-GPe network to transition into the pathological synchronous, rhythmic bursting seen in PD. The model that has dominated the field for the last two decades has assumed that following DA depletion there is an elevation in striatopallidal GABAergic inhibitory input to the GPe, leading to a suppression of this autonomous activity. In the course of pursuing this hypothesis, we discovered that DA depletion induces a change in the intrinsic properties of GPe neurons that results in the loss of autonomous pacemaking. Moverover, this loss appears to be attributable to the down-regulation of a single ion channel subunit (HCN2). It is our central hypothesis that the loss of autonomous pacemaking is responsible for the emergence of synchronous rhythmic bursting of the STN-GPe network in PD and that reversing this adaptation will not only diminish the pathophysiology in this network, it will alleviate the motor symptoms ofPD. This project blends the skills of the labs of Drs. Surmeier, Wilson, Kita and Osten to pursue four specific aims addressing the basic mechanisms underlying this 'silencing' in rodent and monkey models of PD as well as strategies that could be used in PD patients to correct the deficit. Our aims are: 1) to characterize the mechanisms governing the rate and regularity of autonomous pacemaking in GPe neurons and their adaptation in rodent PD models (Wilson); 2) to characterize the mechanisms governing the suppression of pacemaking in GPe neurons in rodent PD models and to develop a means for its restoration (Surmeier, Osten, Kita); 3) to characterize subthalamo-pallidal glutamatergic signaling in rodent PD models and its potential role in suppression of pacemaking (Surmeier); 4) to characterize the role of subthalamo-pallidal synaptic signaling in controlling GPe activity and its adaptations in a monkey model of PD (Kita). Lay summary: 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, gene therapy for late stage PD but open new avenues for pharmacological treatment.

帕金森病 (PD) 是美国第二常见的神经退行性疾病。 PD 的运动症状可归因于中脑多巴胺能神经元的退化 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，神经元 位于基底神经节的两个关键核 - 球核外段 (GPe) 和丘脑底核 (STN) - 同步、高频节律性爆发的尖峰。这种病理生理活动被认为是 导致 PD 患者运动迟缓、运动不能和强直。理论研究表明自主 GPe 神经元的起搏抵消了相互连接的 STN-GPe 的自然趋势 网络转变为 PD 中所见的病理性同步、节律性爆发。该型号有 过去二十年主导该领域的假设是，DA 耗尽后， 纹状体苍白球 GABA 能抑制输入 GPe，导致这种自主活动受到抑制。 在追求这一假设的过程中，我们发现 DA 耗尽会导致内在的变化 GPe 神经元的特性导致自主起搏功能丧失。搬家者，出现这种损失 归因于单个离子通道亚基（HCN2）的下调。这是我们的中心假设 自主起搏的丧失是同步节律爆发出现的原因 STN-GPe 网络在 PD 中的作用，逆转这种适应不仅会削弱病理生理学 在这个网络中，它会减轻PD的运动症状。该项目融合了博士实验室的技能。 Surmeier、Wilson、Kita 和 Osten 致力于实现四个具体目标，解决潜在的基本机制 这种在PD啮齿动物和猴子模型中的“沉默”以及可用于PD患者的策略 纠正赤字。我们的目标是： 1) 描述 GPe 中自主起搏的速率和规律性控制机制 神经元及其在啮齿动物 PD 模型中的适应 (Wilson)； 2) 表征啮齿类PD中GPe神经元起搏抑制的机制 模型并开发修复方法（Surmeier、Osten、Kita）； 3) 表征啮齿类PD模型中的丘脑-苍白球谷氨酸信号传导及其在PD模型中的潜在作用 起搏抑制（Surmeier）； 4) 表征丘脑-苍白球突触信号传导在控制 GPe 活性及其作用中的作用 PD 猴子模型（Kita）的适应。 简单总结：这些研究旨在纠正晚期 PD 中功能失调的大脑活动。这 成功实现我们的目标不仅可以为晚期帕金森病提供一种新颖的基因疗法，而且可以开辟新的途径 药物治疗的途径。