Synaptic pharmacology of single subthalamic neurons

描述（由申请人提供）：丘脑下核（subthalamic nucleus， STN）是基底神经节的一个成员，被认为在帕金森病症状的表达和多巴胺能治疗帕金森病引起的运动障碍的产生中起关键作用。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，但其作用机制仍不清楚。总的来说，关于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）对大鼠脑切片STN神经元的影响。放置在切片中的双极电极将引起STN神经元的兴奋性和抑制性突触电流。为了描述慢性多巴胺消耗所产生的膜特性变化，将对单侧6-羟多巴胺处理大鼠的STN进行记录，并与对照STN进行比较。STN HFS引起的抑制性突触传递的长期变化可能为DBS治疗人类帕金森病的疗效提供模型机制。旨在确定STN中5 -羟色胺的生理作用和受体药理学的实验应该有助于确定这一重要的突触传递调节剂的作用。揭示谷氨酸受体介导的突发放电机制的研究将有助于确定调节STN神经元兴奋性的离子电流。最后，我们计划确定代谢性谷氨酸和n -甲基- d -天冬氨酸受体在正常和多巴胺缺失组织中的相互作用。除了提供关于STN在帕金森病中的作用的新信息外，这些研究的结果也应该与更大的运动障碍领域相关。

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.