Inhibitory Control of Medium Spiny Neurons

中型多棘神经元的抑制控制

• 批准号: 7405633
• 负责人: Kristen Kathleen Foster
• 金额: $ 1.39万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-06 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7405633
• 关键词: Action Potentials; Agonist; Axon; Cells; Class; Confocal Microscopy; Corpus striatum structure; Disease; Dopamine; Dopamine D2 Receptor; Dose; Drug Addiction; Ensure; Excitatory Postsynaptic Potentials; Family; Fire - disasters; Frequencies; Functional disorder; Future; Gilles de la Tourette syndrome; Globus Pallidus; Green Fluorescent Proteins; Huntington Disease; Injection of therapeutic agent; Interneurons; Literature; Measures; Mediating; Modality; Motor; Mouse Strains; Movement; Muscle Rigidity; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurons; Output; Parkinson Disease; Pattern; Population; Property; Proteins; Receptor Activation; Regulation; Reporting; Rest; Rest Tremor; Role; Signal Transduction; Slice; Stream; Substantia nigra structure; Symptoms; Synaptic Receptors; System; Tardive Dyskinesia; Testing; Therapeutic; Thinking; Time; Whole-Cell Recordings; addiction; design; improved; motor impairment; nerve supply; nervous system disorder; novel therapeutics; postsynaptic; receptor; research study; response; selective expression; therapeutic target; voltage

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.

描述（由申请人提供）：本项目旨在比较纹状体苍白球与纹状体黑质中型棘神经元（MSN）中的阶段性和紧张性GABAA受体介导的电流以及介导它们的受体亚型。MSN是GABA能神经元，占纹状体细胞的95%。它们主要从邻近MSN的局部GABA能中间神经元和轴突侧支接收其抑制性输入。纹状体黑质MSN投射到黑质，表达多巴胺D1受体，并且被认为促进运动，而纹状体苍白球MSN投射到苍白球，表达多巴胺D2受体，并且被认为抑制运动。帕金森病（PD）是一种神经系统疾病，其由纹状体的DA神经支配的丧失引起，并且特征在于运动开始受损、静止性震颤、姿势不稳定和僵硬。虽然潜在的机制仍然未知，但大量的研究表明，PD中观察到的运动障碍是由多巴胺能神经支配丧失后D2阳性MSN的过度活跃输出引起的。目前还不清楚为什么增加的输出是选择性的纹状体的MSNs，然而，确定的方法来选择性地减少纹状体的MSNs的活动具有显着的治疗潜力的运动症状的治疗PD。对于本研究，我们将利用从两个品系的小鼠制备的皮质纹状体切片来鉴定介导这些细胞中的抑制电流的受体的独特性质，所述两个品系的小鼠在表达D1或表达D2的细胞中选择性地表达绿色荧光蛋白。将使用单细胞电生理记录结合免疫荧光和共聚焦显微镜来评估介导阶段性和强直性抑制的GABAA受体的特性以及这些电流对细胞兴奋性和NMDA受体激活的功能。除了可能在GABAA受体家族中找到治疗PD的新治疗靶点外，本研究的结果还将显着提高对纹状体回路的了解。这一认识对于帕金森病以及其他纹状体疾病如亨廷顿病、图雷特氏病、迟发性运动障碍和药物成瘾的治疗的未来进展至关重要。