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）：该项目旨在比较阶段性和补品GABAA受体介导的电流以及在纹状体合金与纹状体型培养基棘神经元（MSN）中介导它们的受体亚型。 MSN是GABA能神经元，占纹状体中95％的细胞。他们主要从相邻MSN的局部GABA能中间神经元和轴突侧支中获得抑制作用。纹状体MSNS向黑质，表达多巴胺DL受体，被认为可以促进运动，而纹状体金MSNS向Globus pallidus，表达多巴胺D2受体，并被认为可以抑制运动。帕金森氏病（PD）是一种神经系统疾病，它是由于对纹状体的DA神经的失去而导致的，其特征是运动的开始受损，静止震颤，姿势不稳定和刚性。尽管基本机制仍然未知，但大量研究表明，PD中看到的运动障碍是由D2阳性MSN的过度活跃输出引起的，后者是多巴胺能神经支配的丧失。目前尚不清楚为什么增加的输出对纹状体金属MSN有选择性，但是，确定方法可以选择性地减少纹状体质合MSN的活性具有显着的治疗潜力，以治疗PD中运动症状。在这项研究中，我们将利用由两种小鼠菌株制成的皮质纹状体切片，这些切片在DL表达或表达细胞的DL或D2中选择性表达绿色荧光蛋白来鉴定介导这些细胞中抑制性电流的受体的独特特性。 GABAA受体的特性介导了阶段和补品抑制作用，以及这些电流对细胞兴奋性和NMDA受体激活的功能，将使用单细胞电生理记录与与共摄影显微镜结合结合进行评估。除了潜在地鉴定GABAA受体家族中的新治疗靶标的治疗PD外，这项研究的结果还将显着提高对纹状体电路的理解。这种理解对于PD治疗以及其他纹状体疾病等未来进展至关重要，例如亨廷顿氏病，Tourette's，Tardive Dykinesia和吸毒成瘾。