Synaptic pharmacology of single subthalamic neurons

描述(申请人提供)：丘脑底核(STN)是基底节的一部分，被认为在帕金森病症状的表达和帕金森病多巴胺能治疗引起的运动障碍的产生中发挥关键作用。此外，STN的深部脑刺激(DBS)现在被认为是治疗帕金森病的有效方法，但其作用机制仍存在疑问。总体而言，对调节STN神经元活动的生理和药理学机制知之甚少。我们建议使用标准的全细胞记录技术来表征神经传递的药理学和高频电刺激(HFS)对大鼠脑片STN神经元的影响。放置在切片中的双极电极将在STN神经元中激发兴奋性和抑制性突触电流。为了研究慢性多巴胺耗竭引起的细胞膜特性的变化，我们将在单侧用6-OHDA处理的大鼠的STN中进行记录，并与对照组STN中的记录进行比较。HFS引起的STN抑制性突触传递的长期变化可能为解释DBS治疗人类帕金森病的疗效提供了一种模型机制。旨在确定5-羟色胺在STN中的生理作用和受体药理学的实验应该有助于确定这种重要的突触传递调节器的作用。揭示谷氨酸受体介导的爆发式放电的潜在机制的研究应该有助于确定调节STN神经元兴奋性的离子电流。最后，我们计划在正常和多巴胺耗竭的组织中确定代谢性谷氨酸和N-甲基-D-天冬氨酸受体之间的相互作用。除了提供有关短暂性神经节在帕金森氏病中的作用的新信息外，这些研究的结果也应该与运动障碍的更大领域相关。

DESCRIPTION (provided by applicant): The subthalamic nucleus (STN) is a member of the basal ganglia that is recognized as playing a pivotal role in the expression of symptoms of Parkinson's disease and in the generation of dyskinesia that is caused by dopaminergic treatment of Parkinson's disease. Also, deep brain stimulation (DBS) of the STN is now recognized as an effective treatment of Parkinson's disease, and yet the mechanism of action remains in doubt. In general, little is known about physiological and pharmacological mechanisms that regulate the activity of STN neurons. We propose to use standard whole-cell recording techniques to characterize the pharmacology of neurotransmission and effects of high-frequency electrical stimulation (HFS) on STN neurons in the rat brain slice. Bipolar electrodes placed in the slice will evoke excitatory and inhibitory synaptic currents in STN neurons. In order to characterize changes in membrane properties that are produced by chronic dopamine depletion, recordings will be done in STN from rats treated unilaterally with 6- OHDA, and compared with those obtained in control STN. Long-term changes in inhibitory synaptic transmission caused by HFS of the STN may provide a model mechanism to explain the efficacy of DBS in the treatment of human Parkinson's disease. Experiments designed to define the physiological actions and receptor pharmacology of serotonin in the STN should help define the role of this important modulator of synaptic transmission. Investigations to uncover mechanisms underlying glutamate receptor-mediated burst firing should help define ionic currents that regulate STN neuronal excitability. Finally, we plan to define interactions between metabotropic glutamate and N-methyI-D-aspartate receptors in normal and dopamine depleted tissue. In addition to providing new information on the role of the STN in Parkinson's disease, results from these studies should also be relevant to the greater field of movement disorders.