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

帕金森病（PD）是美国第二大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变性， 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 在基底神经节的两个关键核团--球状体外段（GPe）和丘脑底核中 (STN)- 在同步，高频率的节奏爆发尖峰。这种病理生理活动被认为是 理论研究表明，自主运动是PD患者运动迟缓、运动不能和僵硬的主要原因。 GPe神经元的起搏平衡了STN-GPe连接的自然趋势， 网络过渡到病理同步，节奏爆发看到PD。该模型具有 在过去的二十年里，在该领域占主导地位的人认为，在DA耗尽之后， 纹状体苍白球GABA能抑制性输入GPe，导致这种自主活动的抑制。 在追求这一假设的过程中，我们发现DA耗竭诱导了内源性的变化， GPe神经元的特性导致自主起搏的丧失。翻转，这种损失出现 可能是由于单个离子通道亚基（HCN 2）的下调。我们的核心假设是 自主起搏的丧失是同步节律爆发出现的原因 的STN-GPe网络在PD和逆转这种适应不仅会减少病理生理 在这个网络中，它将减轻PD的运动症状。这个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，解决基本机制 这种“沉默”在啮齿动物和猴子模型的PD以及策略，可用于PD患者， 弥补赤字。我们的目标是： 1)描述GPe中自主起搏的速率和规律性的机制 啮齿动物PD模型中的神经元及其适应（Wilson）; 2)表征啮齿类PD中GPe神经元起搏抑制的机制 模型，并制定一种恢复的手段（Surmeier、Osten、Kita）; 3)表征啮齿动物PD模型中的丘脑底-苍白球神经元能信号传导及其在 抑制起搏（Surmeier）; 4)研究丘脑底-苍白球突触信号在控制GPe活性中的作用， 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。的 我们的目标的成功实现不仅为晚期PD提供了一种新的基因治疗， 药物治疗的途径。

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.