Subunit-specific NMDA receptor function in the subthalamic nucleus

描述（由申请人提供）：帕金森病的衰弱性运动症状与丘脑底核（基底神经节运动回路中的关键结构）中神经元的异常尖峰放电有关。谷氨酸能传入神经元的突触传递对突触神经元的放电频率和模式有重要的调节作用，但是谷氨酸受体在突触传递中的作用还没有得到很好的研究。离子型谷氨酸受体的N-甲基-D-天冬氨酸（NMDA）家族对整个大脑的兴奋性神经传递至关重要。NMDA受体是由两个GluN 1亚基和两个GluN 2亚基（GluN 2A-2D）组成的四聚体，并且GluN 2亚基在脑中显示不同的功能特性以及表达模式。GluN 2B和GluN 2D亚基由神经元表达，然而缺乏GluN 2D选择性化合物限制了对脑中该亚基的研究。新开发的对GluN 2C/D亚基具有选择性的变构调节剂现在将允许研究GluN 2D在帕金森病中的功能以及抑制含GluN 2D的NMDA受体作为治疗策略以纠正帕金森病中帕金森病神经元的异常放电的潜力。本研究将利用膜片钳电生理学和光遗传学方法研究含GluN 2B和GluN 2D的NMDA受体在不同的谷氨酸能输入中的作用。具体的目标是：1）NMDA受体亚型如何控制兴奋性突触传递在解剖学上不同的传入神经元，和2）特定的NMDA受体如何控制紧张性和活动诱导的尖峰放电在海马神经元。这些实验将产生关键数据的作用，NMDA受体在控制海马神经传递和尖峰放电。

DESCRIPTION (provided by applicant): The debilitating motor symptoms in Parkinson's disease are related to aberrant spike firing of neurons in the subthalamic nucleus (STN), a key structure within the basal ganglia motor circuit. Glutamatergic afferents to the STN critically regulate STN neuron firing frequency and pattern; however the functions of specific glutamate receptors in mediating synaptic transmission in the STN have not been well-studied. The N-methyl- D-aspartate (NMDA) family of ionotropic glutamate receptors are critical for excitatory neurotransmission throughout the brain. NMDA receptors are tetramers composed of two GluN1 subunits and two GluN2 subunits (GluN2A-2D), and the GluN2 subunits display different functional properties as well as expression patterns in the brain. The GluN2B and GluN2D subunits are expressed by STN neurons, however the lack of GluN2D-selective compounds has limited the study of this subunit in the brain. Newly developed allosteric modulators that are selective for GluN2C/D subunits will now allow investigation of the function of GluN2D in the STN as well as the potential of inhibition of GluN2D-containing NMDA receptors as a therapeutic strategy to correct the aberrant firing of STN neurons in Parkinson's disease. In this study, patch-clamp electrophysiology and optogenetics will be used to investigate the roles of GluN2B- and GluN2D-containing NMDA receptors at the different glutamatergic inputs to the STN. The specific aims of the proposed work are: 1) how NMDA receptor subtypes control excitatory synaptic transmission at anatomically distinct afferents to the STN, and 2) how specific NMDA receptors control tonic and activity-induced spike firing in STN neurons. These experiments will generate key data on the roles for NMDA receptors in controlling glutamatergic neurotransmission and spike firing in the STN.