Synaptic pharmacology of single subthalamic neurons

描述（申请人提供）：丘脑下核（STN）由谷氨酸神经元组成，驱动基底神经节的输出。此外，STN神经元的动作电位爆发模式与帕金森病的症状有关。然而，调控STN神经元活动的生理和药理学机制还有待进一步研究。利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)通道可显著增加STN神经元的放电速率，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机制产生K-ATP电流的伴随激活。NMDA的这种作用可能是针对STN神经元的，因为NMDA不会在黑质致密部多巴胺神经元中引起K-ATP电流。该资助申请的目的是：1)确定STN神经元中K-ATP电流的受体药理学；2)表征NMDA/K-ATP对膜特性的相互作用；3)鉴定介导K-ATP电流的NMDA激活的第二信使系统；4)表征K-ATP电流对正常大鼠和6-羟多巴胺大鼠帕金森病模型中STN神经元的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受体门控和K-ATP电流调节的理解。结果也可能提示新的方法来药理学上改变STN神经元的活动，这将有利于帕金森病患者。许多研究表明，丘脑下核（STN）神经元过度的突发放电与帕金森病的症状有关。我们的初步研究表明，n -甲基- d -天冬氨酸（NMDA）受体刺激引起的突发放电可以通过同时激活atp敏感的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，我们的研究可能会导致治疗帕金森病症状的新药理学策略。

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.