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

帕金森氏病(PD)是美国第二常见的神经退行性疾病。 帕金森病的运动症状可归因于中脑多巴胺能神经元的变性和 基底节神经元活动的改变。在帕金森病患者和灵长类帕金森病模型中，神经元 在基底节的两个关键核团-球外段(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 负责PD患者的运动迟缓、动作迟缓和僵硬。理论研究表明，自主性 GPE神经元的起搏抵消了相互连接的STN-GPE的自然倾向 网络过渡到帕金森病所见的病理同步、节律性爆发。这款车拥有 在过去20年中主导了这一领域的人认为，随着DA的枯竭， 纹状旁腺素GABA能抑制GPE的输入，导致这种自主活动的抑制。 在追寻这一假说的过程中，我们发现DA的耗竭会导致内源性的改变。 导致自主起搏丧失的GPE神经元的特性。Moverover，这场失利似乎 这可归因于单个离子通道亚单位(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 在帕金森病中STN-GPE网络的变化，逆转这种适应不仅会削弱帕金森病的病理生理学 在这个网络中，它将缓解帕金森病的运动症状。这个项目融合了博士实验室的技能。 苏梅尔、威尔逊、基塔和奥斯汀追求四个具体目标，解决潜在的基本机制 在帕金森病的啮齿动物和猴子模型中，这种“沉默”以及可以用于帕金森病患者的策略 纠正赤字。我们的目标是： 1)描述控制GPE自主起搏速度和规律的机制 神经元及其在啮齿动物帕金森病模型中的适应性(Wilson)； 2)研究帕金森病大鼠GPE神经元起搏抑制的机制 建立模型并开发修复方法(苏梅尔、奥斯汀、基塔)； 3)研究帕金森病大鼠模型下丘脑-苍白球谷氨酸能信号的特点及其在帕金森病发病机制中的作用。 抑制起搏(Surmeier)； 4)研究丘脑下部-苍白球突触信号在控制GPE活性中的作用及其 帕金森病(KITA)猴模型的适应性。 总结：这些研究旨在纠正晚期帕金森病患者的脑活动障碍。这个 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基因治疗方法，而且可以打开新的 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.