Subunit-specific NMDA receptor function in the subthalamic nucleus

描述(申请人提供)：帕金森病的衰弱运动症状与丘脑底核(STN)神经元的异常棘波放电有关，STN是基底神经节运动回路的关键结构。STN的谷氨酸能传入对STN神经元的放电频率和模式起着重要的调节作用，然而，特异性谷氨酸受体在STN中介导突触传递的作用尚未得到很好的研究。N-甲基-D-天冬氨酸(NMDA)家族的离子亲和性谷氨酸受体对于整个大脑的兴奋性神经传递是至关重要的。NMDA受体是由两个GluN1亚基和两个GluN2亚基(GluN2A-2D)组成的四聚体，GluN2亚基在脑中表现出不同的功能特性和表达模式。GluN2B和GluN2D亚基由STN神经元表达，然而GluN2D选择性化合物的缺乏限制了对该亚基在大脑中的研究。新开发的变构调节剂对GluN2C/D亚基具有选择性，现在可以研究GluN2D在STN中的功能，以及抑制含有GluN2D的NMDA受体的潜力，作为纠正帕金森病STN神经元异常放电的治疗策略。在这项研究中，我们将利用膜片钳电生理学和光遗传学的方法，研究含GluN2B和GluN2D的NMDA受体在不同谷氨酸能传入STN中的作用。这项工作的具体目标是：1)NMDA受体亚型如何控制在解剖上不同的STN传入的兴奋性突触传递，以及2)特定的NMDA受体如何控制STN神经元的紧张性和活动诱导的放电。这些实验将产生关于NMDA受体在控制STN中的谷氨酸能神经传递和棘波放电中所起作用的关键数据。

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.