CELLULAR AND MOLECULAR MECHANISMS GOVERNING RHYTHMICITY AND SYNCHRONY IN NEURONS

控制神经元节律和同步的细胞和分子机制

• 批准号: 6822361
• 负责人: DALTON JAMES SURMEIER
• 金额: $ 21.7万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6822361
• 关键词: Parkinson's disease; basal ganglia; biological signal transduction; biophysics; brain electrical activity; dopamine; gamma aminobutyrate; gene targeting; genetically modified animals; laboratory mouse; lenticular nucleus; membrane channels; membrane potentials; messenger RNA; neural degeneration; neural transmission; neurologic manifestations; neuropharmacology; neuroregulation; polymerase chain reaction; psychomotor function; sodium channel; subthalamus; synapses; voltage /patch clamp

Parkinson's disease (PD) afflicts roughly 1 in 1000 adults, rising exponentially in incidence after the age of fifty. Human and animal studies have shown that parkinsonism results from the degeneration of the mesencephalic dopaminergic neurons. In PD patients and in primate PD models, the electrical activity of neurons in external globus pallidus (GPe) is abnormal. Unlike neurons from normal animals, GPe neurons in these animals exhibit synchronous, rhythmic burst discharges. It is our working hypothesis that this abnormal activity is attributable to adaptations in intrinsic properties of GPe neurons and their synaptic input following dopamine (DA) depletion. In the last grant period, our work focused on intrinsic properties controlling repetitive firing of GPe and STN neurons. In this upcoming award period, we plan to build upon these studies and those of other program participants to provide a more complete understanding of the mechanisms controlling rhythmic activity and synchrony in GPe neurons. Specifically, a combination of cellular and molecular approaches will be used to address two specific aims that are natural extensions of the aims in the previous grant period. Our first specific aim is to characterize the role of intrinsic, voltage-dependent Na+ and HCN channels in controlling rhythmic activity in identified GPe neurons in normal and dopamine-depleted mice. It is our working hypothesis that Na+/HCN channels are primary determinants of rhythmic discharge in GPe neurons. The molecular, biophysical and pharmacological properties of these channels and their susceptibility to modulation will be characterized using a combination of electrophysiological, biochemical and scRT-PCR approaches in neurons derived from wild-type, transgenic/knockout and dopamine-depleted mice.Our second specific aim is to characterize the role of GABAergic signaling in controlling activity patterning and synchrony in identified GPe neurons in normal and dopamine-depleted mice. Modeling work sponsored by this PPG predicts that diminished intrapallidal and increased striatal GABAergic input to GPe neurons may be a major factor in the emergence ofsynchrony and burst firing. To test this hypothesis, a combination of electrophysiological, pharmacological and scRT-PCR approaches will be used in neurons derived from wild-type, transgenic/knockout and dopamine-depleted mice. The successful attainment of these specific aims should provide much needed information about the properties of normal and dopamine-depleted GPe neurons - placing the neuroscience community in a much better position to devise new and more effective pharmacological and genetic treatments for Parkinson's disease.

帕金森氏症（PD）的发病率约为千分之一，50岁以后发病率呈指数级上升。人类和动物研究表明，帕金森病是由中脑多巴胺能神经元的退化引起的。在PD患者和灵长类PD模型中，外苍白球（GPe）神经元的电活动异常。与正常动物的神经元不同，这些动物的GPe神经元表现出同步的、有节奏的突发放电。我们的工作假设是，这种异常活动可归因于GPe神经元内在特性的适应及其多巴胺（DA）消耗后的突触输入。