Synaptic pharmacology of single subthalamic neurons

单个底丘脑神经元的突触药理学

• 批准号: 7844801
• 负责人: STEVEN WILLIAM JOHNSON
• 金额: $ 27.29万
• 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 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7844801
• 关键词: Action Potentials; Applications Grants; Basal Ganglia; Brain; Calcium; Cells; Cyclic GMP; Data; Dopamine; Functional disorder; Glutamates; Goals; Guanylate Cyclase; Lead; Learning; Mediating; Membrane; Modeling; Movement Disorders; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurons; Nitric Oxide; Nitric Oxide Synthase; Output; Oxidopamine; Parkinson Disease; Patch-Clamp Techniques; Patients; Pattern; Pharmacology; Physiological; Physiology; Play; Process; Property; Rattus; Receptor Activation; Regulation; Reverse Transcription; Role; Second Messenger Systems; Slice; Structure of subthalamic nucleus; Substantia nigra structure; Sulfonylurea Compounds; Symptoms; Synapses; Techniques; Testing; Tissues; Tolbutamide; dopaminergic neuron; improved; neuronal excitability; neurophysiology; pars compacta; patch clamp; prevent; public health relevance; receptor; research study; treatment strategy

DESCRIPTION (provided by applicant): The subthalamic nucleus (STN) is composed of glutamate-containing neurons that drive the output of the basal ganglia. Moreover, the bursting pattern of action potentials in STN neurons has been associated with symptoms of Parkinson's disease. However, there is much to be learned about physiological and pharmacological mechanisms that regulate the activity of STN neurons. Using standard whole-cell patch-clamp recording techniques in slices of rat brain, our preliminary data show that blocking of the ATP-sensitive K+ (K-ATP) channels significantly increases firing rate, prolongs depolarizing plateau potentials, and augments N-methyl-D-aspartate (NMDA)-induced burst firing in STN neurons. Moreover, we present data suggesting that NMDA receptor stimulation produces concomitant activation of K-ATP current by a nitric oxide- dependent mechanism. This effect of NMDA might be specific for STN neurons because NMDA does not evoke K-ATP currents in substantia nigra pars compacta dopamine neurons. The aims of this grant application are to 1) define the receptor pharmacology of K-ATP currents in STN neurons, 2) characterize NMDA/K-ATP interactions on membrane properties, 3) identify second messenger systems that mediate NMDA activation of K-ATP currents, and 4) characterize the influence of K-ATP currents on excitability and firing patterns of STN neurons from normal rats as well as in a 6-hydroxydopamine rat model of Parkinson's disease. Our proposed studies will significantly increase our understanding of how STN neurons are regulated by NMDA receptor- gated and K-ATP currents. Results may also suggest new ways to pharmacologically modify STN neuronal activity that would benefit patients with Parkinson's disease. PUBLIC HEALTH RELEVANCE Many studies suggest that excessive burst firing in subthalamic nucleus (STN) neurons contributes to symptoms of Parkinson's disease. Our preliminary studies show that burst firing that is evoked by N-methyl-D-aspartate (NMDA) receptor stimulation can be inhibited by concomitant activation of inhibitory currents generated by ATP-sensitive K+ (K-ATP) channels. By better understanding the interplay between NMDA and K-ATP currents in the STN, our studies may lead to new pharmacological strategies for the treatment of Parkinson's disease symptoms.

描述（由申请人提供）：丘脑底核（STN）由驱动基底神经节输出的含谷氨酸神经元组成。此外，STN 神经元动作电位的爆发模式与帕金森病的症状有关。然而，关于调节 STN 神经元活性的生理和药理学机制，还有很多东西需要了解。在大鼠脑切片中使用标准全细胞膜片钳记录技术，我们的初步数据表明，阻断 ATP 敏感的 K+ (K-ATP) 通道可显着提高放电速率，延长去极化平台电位，并增强 STN 神经元中 N-甲基-D-天冬氨酸 (NMDA) 诱导的爆发放电。此外，我们提供的数据表明，NMDA 受体刺激通过一氧化氮依赖性机制产生 K-ATP 电流的伴随激活。 NMDA 的这种作用可能是 STN 神经元特有的，因为 NMDA 不会在黑质致密部多巴胺神经元中引起 K-ATP 电流。本拨款申请的目的是 1) 定义 STN 神经元中 K-ATP 电流的受体药理学，2) 表征 NMDA/K-ATP 相互作用对膜特性的影响，3) 确定介导 K-ATP 电流 NMDA 激活的第二信使系统，4) 表征 K-ATP 电流对正常大鼠和大鼠 STN 神经元兴奋性和放电模式的影响。 6-羟基多巴胺帕金森病大鼠模型。我们提出的研究将显着增加我们对 STN 神经元如何受 NMDA 受体门控和 K-ATP 电流调节的理解。研究结果还可能提出从药理学上改变 STN 神经元活性的新方法，这将使帕金森病患者受益。公共健康相关性 许多研究表明，丘脑底核 (STN) 神经元的过度爆发放电会导致帕金森病的症状。我们的初步研究表明，N-甲基-D-天冬氨酸 (NMDA) 受体刺激引起的爆发放电可以通过同时激活 ATP 敏感 K+ (K-ATP) 通道产生的抑制电流来抑制。通过更好地了解 STN 中 NMDA 和 K-ATP 电流之间的相互作用，我们的研究可能会带来治疗帕金森病症状的新药理学策略。