Ih电流——帕金森病异常HVSs节律的离子机制

项目名称： Ih电流——帕金森病异常HVSs节律的离子机制

项目编号： No.81471342

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 朱俊玲

作者单位： 中国人民解放军第四军医大学

项目金额： 70万元

中文摘要： 皮层-基底节(BG)环路的异常振荡与帕金森病(PD)有直接关系,6-OHDA PD模型大鼠存在皮层-BG环路的HVSs节律异常,机制不明。细胞水平的神经元膜共振是网络水平神经振荡的基础。我们首次证实,正常大鼠BG区神经元存在超极化激活的阳离子流(Ih)介导的膜共振。而PD模型的BG区神经元HCN2通道下调。故提出假设:PD大鼠BG区神经元Ih电流减小,导致膜共振减弱,引发皮层-BG环路HVSs节律异常。即,Ih电流是PD异常HVSs节律的离子机制。本项目拟采用膜片钳及场电位记录技术,聚焦丘脑底核(STN):明确PD大鼠STN神经元Ih电流及膜共振发生变异；用药理学和重组病毒对STN局部操控，下调正常大鼠/上调PD大鼠的Ih电流或HCN2通道，考察对膜共振的影响、对HVSs节律的作用、及其行为相关性。这是从新的角度对HVSs节律异常机制的新探索，可能会在PD病理机制上有所突破，具有重要意义。

中文关键词： 帕金森病；超极化激活的阳离子电流；HVSs节律；共振；振荡

英文摘要： Pathological oscillations in the cortex-BG loop are potentially causal to motor deficits in Parkinson's disease (PD). High-voltage spindles (HVSs) are 5- to 13-Hz oscillations with a characteristic spike-and-wave shape. They occur spontaneously in awake rats when the animal is quietly resting. It was shown in literature and our previous study that dopaminergic lesion resulted in a significant enhancement of HVSs in the cortex-BG loop in 6-OHDA PD rats. The exact mechanism underlying abnormal HVSs in PD still remain unclear. Intrinsic resonance properties of individual neurons provide a basis for network oscillations. We demonstrated for the first time that theta-frequency resonance properties were mediated by hyperpolarization-activated cation current (I(h)) in neurons of substantia nigra pars compacta (SNc), subthalamic nucleus (STN), and globus pallidus (GP). And downregulations of hyperpolarization and cyclic nucleotide-gated (HCN) channel expression were found in GP and STN neurons in PD models. Therefore we put forward a hypothesis: In PD rats, Ih current in BG neurons might decrease, membrane resonance might weaken, and in turn HVSs rhythm might be abnormal in cortex-BG loop. That is, Ih current is the ionic mechanism underlying abnormal HVSs rhythm in PD. This project intends to use the patch clamp and local field potential recording techniques, and focus on STN: (1)To make clear that Ih current and membrane resonance are altered in STN neurons of PD model rats. (2)By pharmacological methods or virus transfection to manipulate STN neurons, downregulating Ih current or HCN2 channel expression in control rats / upregulating Ih current or HCN2 channel expression in PD rats, to observe the effects on the membrane resonance, HVSs rhythm and related behavior. This is a new exploration to the mechanism underlying abnormal HVSs from a new point of view, and may bring a breakthrough in the pathophysiology of PD, being of vital significance.

英文关键词： Parkinson's disease;Hyperpolarization-activated cation current;High voltage spindles;Resonance;Oscillation