Inhibitory Control of Medium Spiny Neurons

描述（由申请人提供）：本项目旨在比较纹状体与纹状体中棘神经元（MSNs）中GABAA受体介导的相位和张力电流及其受体亚型。msn是gaba能神经元，占纹状体细胞的95%。它们主要从局部gaba能中间神经元和邻近msn的轴突侧枝接受抑制输入。纹状体的msn投射到黑质，表达多巴胺D2受体，被认为促进运动，而纹状体的msn投射到苍白球，表达多巴胺D2受体，被认为抑制运动。帕金森病（PD）是一种由纹状体DA神经支配丧失引起的神经系统疾病，其特征是运动启动受损、静息性震颤、姿势不稳定和僵硬。尽管其潜在的机制尚不清楚，但大量研究表明，PD患者的运动障碍是由于多巴胺能神经支配丧失后D2阳性msn的过度输出引起的。目前尚不清楚为什么增加的输出是选择性的纹状状单抗神经网络，然而，确定选择性降低纹状状单抗神经网络活性的方法对治疗帕金森病的运动症状具有重要的治疗潜力。在这项研究中，我们将利用两种小鼠的皮质纹状体切片，这些小鼠在表达Dl或D2的细胞中选择性地表达绿色荧光蛋白，以鉴定在这些细胞中介导抑制电流的受体的独特特性。利用单细胞电生理记录，结合共聚焦显微镜的免疫荧光技术，评估GABAA受体介导的相位和张力抑制的特性，以及这些电流对细胞兴奋性和NMDA受体激活的作用。除了潜在地发现GABAA受体家族治疗PD的新治疗靶点外，本研究的结果将显著提高对纹状体回路的理解。这一认识对于PD以及其他纹状体疾病（如亨廷顿病、妥瑞氏症、迟发性运动障碍和药物成瘾）治疗的未来进展至关重要。

DESCRIPTION (provided by applicant): This project aims to compare phasic and tonic GABAA receptor-mediated currents and the receptor subtypes that mediate them in striatopallidal versus striatonigral medium spiny neurons (MSNs). MSNs are GABAergic neurons which make up 95% of the cells in the striatum. They primarily receive their inhibitory input from local GABAergic interneurons and axon collaterals of neighboring MSNs. The striatonigral MSNs project to the substantia nigra, express dopamine Dl receptors and are thought to facilitate movement whereas the striatopallidal MSNs project to the globus pallidus, express dopamine D2 receptors and are thought to inhibit movement. Parkinson's disease (PD) is a neurological disorder that results from a loss of DA innervation to the striatum and is characterized by impaired initiation of movement, resting tremor, postural instability and rigidity. Although the underlying mechanism remains unknown, an abundance of studies have suggested that the motor impairments seen in PD arise from an overactive output of the D2 positive MSNs that follows loss of dopaminergic innervation. It is unclear why the increased output is selective for the striatopallidal MSNs, however, identifying ways to selectively reduce the activity of the striatopallidal MSNs holds significant therapeutic potential for the treatment of the motor symptoms in PD. For this study, we will utilize corticostriatal slices made from two strains of mice which selectively express green fluorescent protein in either Dl expressing or D2 expressing cells to identify unique properties of receptors that mediate inhibitory currents in these cells. The properties of the GABAA receptors which mediate both the phasic and the tonic inhibition as well as the function of these currents on cell excitability and NMDA receptor activation will be assessed using single cell electrophysiological recordings in conjunction with immunofluoresence with confocal microscopy. In addition to potentially identifying new therapeutic targets in the GABAA receptor family for treatment of PD, the results of this study will significantly improve the understanding of striatal circuitry. This understanding is fundamental for future progress in treatment of PD as well as other striatal disorders like Huntington's disease, Tourette's, tardive dyskinesia and drug addiction.