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.

谷氨酸能亚丘脑下核（STN）是正常自愿运动和运动障碍中基底神经节中神经元活性的主要驱动力，例如在帕金森氏病（PD）中。在PD的特发性和实验模型中，STN神经元显示出异常的活性模式，这可能部分是由于其内在膜特性的改变而产生的。 STN中的细胞可塑性可能是由于在STN和/或突触输入的改变模式内的多巴胺能神经调节丧失而导致的，这是由于其他基底神经节核中多巴胺的消耗而导致的。第一个具体目的是进一步确定STN神经元在体外（即自发振荡，驱动的高频活性和反弹爆发激发）的正常发射特性的基础的离子，生物物理和分子原理。这将使用STN的电流和电压钳记录来实现 使用斑块夹技术的穿孔，全细胞和成核构型在体外进行神经元。特定离子通道在发射行为中的作用将通过在存在选择性通道阻滞剂的情况下检查发射和离子电流而受到尊重，使用Alpha亚基和Messenger RNA表达研究的免疫细胞化学，将确定STN神经元中离子通道的分子性质。第二个具体目的是确定多巴胺如何调节STN神经元的点火和离子通道特性。这将使用上述上述的电生理和分子方法来解决，多巴胺将通过选择性D1样和D2样受体激动剂来确定离子通道的神经调节。正常和多巴胺中STN神经元的膜特性 然后将进行比较，以确定细胞可塑性是否有助于PD中STN神经元的异常活性。