Synaptic pharmacology of single subthalamic neurons

描述(申请人提供)：丘脑底核(STN)由驱动基底节输出的谷氨酸神经元组成。此外，STN神经元中动作电位的爆发模式与帕金森氏病的症状有关。然而，关于调节STN神经元活动的生理和药理学机制还有很多需要了解。在大鼠脑片上采用标准的全细胞膜片钳记录技术，我们的初步数据显示，阻断ATP敏感的K(K-ATP)通道显著增加STN神经元的放电频率，延长去极化平台电位，并增强N-甲基-D-天冬氨酸(NMDA)诱导的突发性放电。此外，我们提供的数据表明，NMDA受体刺激通过一氧化氮依赖的机制产生伴随的K-ATP电流激活。NMDA的这种作用可能是STN神经元所特有的，因为NMDA不能在黑质致密部的多巴胺神经元上诱发K-ATP电流。这项拨款申请的目的是1)确定STN神经元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)识别介导K-ATP电流NMDA激活的第二信使系统，以及4)表征K-ATP电流对正常大鼠和6-羟基多巴胺帕金森病大鼠模型STN神经元兴奋性和放电模式的影响。我们提出的研究将显著增加我们对STN神经元如何受NMDA受体门控电流和K-ATP电流调节的理解。研究结果还可能提出新的方法，从药物上改变STN神经元的活动，从而使帕金森氏症患者受益。公共卫生相关性许多研究表明，丘脑底核(STN)神经元过度的爆发性放电与帕金森病的症状有关。我们的初步研究表明，刺激N-甲基-D-天冬氨酸(NMDA)受体引起的猝发放电可以被ATP敏感的K(K-ATP)通道产生的抑制电流同时激活所抑制。通过更好地了解STN中NMDA和K-ATP电流之间的相互作用，我们的研究可能会导致治疗帕金森病症状的新的药理学策略。

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.