Molecular analysis of neural circuit excitation and inhibition

神经回路兴奋和抑制的分子分析

• 批准号: 9014139
• 负责人: MICHAEL M FRANCIS
• 金额: $ 41.88万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9014139
• 关键词: Acetylcholine; Address; Affect; Alzheimer' s Disease; Animal Model; Area; Binding; Biological; Biological Models; Biology; Brain; Caenorhabditis elegans; Cells; Cholinergic Receptors; Clinical; Collection; Communication; Defect; Dendrites; Dense Core Vesicle; Development; Disease; Drug Targeting; Epilepsy; Equilibrium; Funding; Genetic; Goals; Health; Hippocampus (Brain); Human; Inhibitory Synapse; Interneurons; Knowledge; Link; Maintenance; Mediating; Molecular; Molecular Analysis; Molecular Genetics; Motor; Motor Neurons; Movement; Nematoda; Nervous system structure; Neuromuscular Junction; Neurons; Neurotransmitter Receptor; Neurotransmitters; Nicotine; Nicotine Dependence; Nicotinic Receptors; Output; Pathway interactions; Pattern; Physiology; Play; Process; Regulation; Resolution; Role; Schizophrenia; Shapes; Signal Pathway; Signal Transduction; Site; Spinal Cord; Synapses; Synaptic Transmission; System; Therapeutic; Work; cholinergic; cholinergic neuron; cohort; design; excitatory neuron; gamma-Aminobutyric Acid; genetic approach; in vivo; inhibitory neuron; insight; molecular dynamics; mutant; nerve supply; nervous system disorder; neural circuit; neuropsychiatry; neurotransmitter release; novel; postsynaptic; presynaptic; presynaptic neurons; receptor; receptor function; relating to nervous system; research study; success; synaptic function; synaptogenesis; tool; trafficking; transmission process; vesicular release

 DESCRIPTION (provided by applicant): Cholinergic signaling mediated by ionotropic (nicotinic) acetylcholine receptors (iAChRs) plays key roles in the mammalian nervous system. iAChRs modulate neurotransmitter release at diverse synapse types across virtually every area of the brain and spinal cord, and in addition, regulate the activity of inhibitory interneurons in critical brain areas. Alterations in iAChR signaling are associated with a number of debilitating neurological disorders including Alzheimer's disease, schizophrenia and certain forms of epilepsy. Moreover, nicotine binding to nicotinic receptors in the nervous system initiates the cellular and molecular cascade that results in nicotine addiction. Despite the clear importance of iAChR signaling in normal brain physiology and health, there are major gaps in our understanding of the cellular mechanisms that regulate cholinergic signaling in the brain. We have made the exciting observation that iAChRs also regulate inhibitory neuron activity in the genetically tractable model organism Caenorhabditis elegans. We have developed a powerful system to study the trafficking, localization and function of these receptors in the dendrites of inhibitory neurons located in a simple 3-layer circuit that controls C. elegans movement. This proposal aims to use the genetic tools we have generated for manipulation of activity levels in this circuit, along with the powerful array of molecular genetic approaches available in C. elegans, to explore fundamental questions in iAChR biology. In this project we will (Aim 1) characterize iAChR subcellular localization, subunit composition, in vivo dynamics, and molecular pathways responsible for delivery of iAChRs to specific subcellular domains on inhibitory neurons; (Aim 2) investigate how altered cholinergic innervation of GABA neurons leads to defects in the development or maintenance of GABA synapses; (Aim 3) determine the role of a novel neurexin signaling pathway in shaping GABA synapse development. We expect that our studies of this experimentally tractable circuit in the worm will provide exciting new insights into mechanisms for biological regulation of iAChRs in the brain, and their important roles in regulating inhibitory signaling. Additionally, the identification and functional characterization of conserved genetic pathways that regulate synapse formation and function in our experiments will ultimately yield novel drug targets for therapeutic strategies designed to treat neurological disorders involving cholinergic signaling.

 描述（由申请人提供）：由离子型（烟碱型）乙酰胆碱受体（iAChR）介导的胆碱能信号传导在哺乳动物神经系统中起关键作用。iAChR在大脑和脊髓的几乎每个区域的不同突触类型处调节神经递质释放，此外，还调节关键大脑区域中抑制性中间神经元的活性。iAChR信号传导的改变与许多使人衰弱的神经系统疾病有关，包括阿尔茨海默病、精神分裂症和某些形式的癫痫。此外，尼古丁与神经系统中的烟碱受体结合，启动导致尼古丁成瘾的细胞和分子级联反应。尽管iAChR信号在正常大脑生理和健康中具有明显的重要性，但我们对调节大脑胆碱能信号的细胞机制的理解存在重大差距。我们已经取得了令人兴奋的观察，iAChRs也调节抑制性神经元活动的遗传听话的模式生物秀丽隐杆线虫。我们已经开发了一个强大的系统来研究这些受体在抑制性神经元树突中的运输、定位和功能，这些神经元位于控制C。优雅运动这项建议旨在使用我们已经产生的遗传工具来操纵这个回路中的活性水平，沿着的是在C. elegans，探索iAChR生物学的基本问题。在本研究中，我们将（目的1）研究iAChR的亚细胞定位、亚基组成、体内动力学和将iAChR传递到抑制性神经元上特定亚细胞区域的分子通路;（目的2）研究GABA神经元胆碱能神经支配的改变如何导致GABA突触发育或维持的缺陷;（3）确定一条新的neurexin信号通路在GABA突触发育中的作用。我们期望我们对蠕虫中这种实验上易于处理的回路的研究将为大脑中iAChR的生物调节机制及其在调节抑制性信号传导中的重要作用提供令人兴奋的新见解。此外，在我们的实验中，对调节突触形成和功能的保守遗传途径的鉴定和功能表征将最终产生用于治疗涉及胆碱能信号传导的神经系统疾病的治疗策略的新型药物靶点。