DYNAMIC PROPERTIES OF ION CHANNELS IN THE SUBTHALAMUS

底丘脑离子通道的动态特性

• 批准号: 6822362
• 负责人: Mark D Bevan
• 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/6822362
• 关键词: Parkinson's disease; basal ganglia; biophysics; brain electrical activity; calcium channel; dopamine; dopamine receptor; gene targeting; genetically modified animals; homovanillate; immunocytochemistry; laboratory mouse; laboratory rat; lenticular nucleus; membrane channels; membrane potentials; messenger RNA; neural plasticity; neural transmission; neurologic manifestations; neuroregulation; polymerase chain reaction; sodium channel; subthalamus; synapses

The glutamatergic subthalamic nucleus (STN) is a major driving force of neuronal activity in the basal ganglia during normal voluntary movement and in movement disorders e.g. in Parkinson's disease (PD). In idiopathic and experimental models of PD, STN neurons display abnormal patterns of activity, which may arise, in part, from an alteration in their intrinsic membrane properties. Cellular plasticity in the STN may result from the loss of dopaminergic neuromodulation within the STN and/or the altered pattern of synaptic input, which results from the depletion of dopamine in other basal ganglia nuclei. The first specific aim is to determine further the ionic, biophysical and molecular principles that underlie the normal firing properties of STN neurons in vitro i.e., spontaneous oscillation, driven high-frequency activity and rebound burst firing. This will be achieved using current- and voltage-clamp recording of STN neurons in vitro using the perforated, whole-cell and nucleated configurations of the patch clamp technique. The roles of specific ion channels in firing behavior will be adressed by examination of firing and ionic currents in the presence of selective channel blockers, the molecular nature of ion channels in STN neurons will be determined using immunocytochemistry of alpha subunits and messenger RNA expression studies. The second specific aim is to determine how dopamine modulates the firing and ion channel properties of STN neurons. This will be addressed using the combined electrophysiological and molecular approach described above, the neuromodulation of ion channels by dopamine will be determined using selective D1-like and D2-like receptor agonists. The membrane properties of STN neurons in normal and dopamine-depleted animals will then be compared to determine whether cellular plasticity contributes to the abnormal activity of STN neurons in PD.

丘脑底核（subthalamic nucleus，简称TH）是正常自主运动和运动障碍（如帕金森病（Parkinson's disease，PD））中基底神经节神经元活动的主要驱动力。在帕金森病的特发性和实验性模型中，帕金森病神经元显示出异常的活动模式，这可能部分是由于其固有膜特性的改变。中脑中的细胞可塑性可能是由于中脑内多巴胺能神经调节的丧失和/或突触输入模式的改变，这是由于其他基底神经节核中多巴胺的耗尽。第一个具体目标是进一步确定体外神经元正常放电特性的离子、生物物理和分子原理，即，自发振荡、驱动高频活动和反弹爆发放电。这将通过使用电流钳和电压钳记录 使用膜片钳技术的穿孔、全细胞和有核配置在体外的神经元。通过在选择性通道阻断剂存在下检查放电和离子电流来探讨特定离子通道在放电行为中的作用，将使用α亚单位的免疫细胞化学和信使RNA表达研究来确定突触神经元中离子通道的分子性质。第二个具体目标是确定多巴胺如何调节突触神经元的放电和离子通道特性。这将使用上述组合的电生理学和分子方法来解决，多巴胺对离子通道的神经调节将使用选择性D1样和D2样受体激动剂来确定。正常和多巴胺缺乏大鼠海马神经元的膜特性 然后将动物进行比较以确定细胞可塑性是否有助于PD中神经元的异常活动。