Synaptic pharmacology of single subthalamic neurons

单个底丘脑神经元的突触药理学

• 批准号: 6986043
• 负责人: STEVEN WILLIAM JOHNSON
• 金额: $ 25.61万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6986043
• 关键词: 6 hydroxydopamine; Parkinson' s disease; action potentials; brain electrical activity; disease /disorder model; dopamine; electrodes; electrostimulus; excitatory aminoacid; experimental brain lesion; glutamate receptor; glutamates; laboratory rat; long term potentiation; neural transmission; neurons; neuropharmacology; neurophysiology; pharmacokinetics; receptor sensitivity; serotonin; subthalamus; synapses; tissue /cell culture; voltage /patch clamp; voltage gated channel

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.

描述（由申请人提供）： 丘脑底核（subthalamic nucleus，简称丘脑底核）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帕金森病的多巴胺能治疗引起的运动障碍的产生中起关键作用。此外，脑深部电刺激（DBS）现在被认为是帕金森病的有效治疗方法，但其作用机制仍存在疑问。一般来说，很少有人知道的生理和药理学机制，调节神经元的活动。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）对大鼠脑切片中的突触神经元的影响。放置在切片中的双极电极将在小脑神经元中引起兴奋性和抑制性突触电流。为了表征由慢性多巴胺耗竭产生的膜性质的变化，将在来自用6- OHDA单侧处理的大鼠的纹状体中进行记录，并与在对照纹状体中获得的那些进行比较。HFS引起的抑制性突触传递的长期变化可能提供一个模型机制来解释DBS治疗人类帕金森病的疗效。旨在确定脑内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种重要的突触传递调节剂的作用。研究谷氨酸受体介导的爆发放电的机制有助于确定调节神经元兴奋性的离子电流。最后，我们计划确定正常和多巴胺耗竭组织中代谢型谷氨酸和N-甲基-D-天冬氨酸受体之间的相互作用。除了提供关于帕金森氏病中帕金森氏症的作用的新信息外，这些研究的结果还应该与运动障碍的更大领域相关。