The role of intrinsic variability in the synchronization of pallidal neurons

描述(申请人提供)：苍白球的GABA能神经元在帕金森病的症状中起着重要作用。具体地说，在帕金森氏病中，这些神经元以同步的方式发射动作电位，有助于基底节的整体振荡。在正常情况下，这些神经元有一个有趣的特性，它们以可靠和有节奏的方式产生自己的动作电位，但在放电模式上有一些不规律。Pallidal神经元彼此突触耦合，并共享来自纹状体的一些GABA能输入；激活共享输入可短暂同步神经元的活动，直到内在变异性使神经元相互发射异相。因此，控制自主放电模式中的可变性的机制可能会影响这些神经元如何同步到共享的输入。产生放电模式的离子通道处于影响自主疲劳模式的可变性或精确度的关键位置。因此，这项研究的目标是确定控制苍白球神经元放电精确度的离子通道，并确定它们的药物阻断是否会影响苍白球神经元在共同输入后的同步方式。电生理记录将在体外切片制备中进行，这将使我们能够使用药理学来识别离子通道并确定关键的离子通道属性。这些数据将被用来构建一个苍白球神经元的计算机模型，以现实的方式复制观察到的变异性。来自神经元对的录音和对网络模型的分析将被用来进一步确定离子通道的可用性如何影响同步。在帕金森氏症中，苍白球中的神经元同步它们的电活动，但导致这一过程的机制尚不清楚。这些研究将调查特定离子通道在创建或限制同步中的作用。了解这些离子通道的作用可能会通过确定潜在的治疗靶点来指导治疗帕金森氏症症状的新疗法。

DESCRIPTION (provided by applicant): GABAergic neurons of the globus pallidus play a significant role in the symptoms of Parkinson's disease. Specifically these neurons fire action potentials in a synchronized fashion in Parkinson's disease, contributing to global oscillations seen in the basal ganglia. Under normal conditions these neurons have an interesting property in that they generate their own action potentials in a reliable and rhythmic fashion, but there is some irregularity in the firing pattern. Pallidal neurons are synaptically coupled with one another and share some GABAergic input from the striatum; activating a shared input briefly synchronizes the activity of neurons until intrinsic variability makes the neurons fire out of phase from one another. Therefore, the mechanisms that control variability in the autonomous firing pattern could influence how these neurons synchronize to a shared input. Ion channels that generate the firing pattern are in a key position to influence the variability or precision of the autonomous tiring pattern. Thus, the goals of the proposed studies are to identity the ion channels that control the precision of firing in pallidal neurons and to determine if their pharmacological blockade can influence the way pallidal neurons synchronize after a common input. Electrophysiological recordings will be made in an in vitro slice preparation which will allow us to identify ion channels using pharmacology and determine key ion channel properties. This data will be used to construct a computer model of a pallidal neuron that replicates the observed variability in a realistic way. Recordings from pairs of neurons and analysis of a network model will be used to further determine how the availability of ion channels affects synchrony. Neurons in the globus pallidus synchronize their electrical activity in Parkinson's disease, but the mechanisms leading to this are not known. These studies will investigate the role of specific ion channels in creating or limiting synchronization. Understanding these ion channel's role could lead to new therapies for the symptoms of Parkinson's disease by identifying potential therapeutic targets.