Mechanisms for synaptic localization of ionotropic GABA receptors in the brain

大脑中离子型 GABA 受体突触定位的机制

• 批准号: 10056230
• 负责人: Susumu Tomita
• 金额: $ 41.88万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-15 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10056230
• 关键词: Brain; Brain Diseases; Cell Adhesion Molecules; Cellular biology; Complex; Disease; Epilepsy; Functional disorder; GABA Receptor; Glutamate Receptor; Glutamates; Goals; Health; Heterogeneity; Human; Impairment; Inhibitory Synapse; Knockout Mice; Knowledge; Laboratories; Link; Mediating; Mental disorders; Molecular; Neurobiology; Neurons; Neurotransmitter Receptor; Play; Positioning Attribute; Presynaptic Terminals; Property; Protein Family; Regulation; Research; Role; Schizophrenia; Site; Synapses; Synaptic Receptors; Synaptic Transmission; Work; autism spectrum disorder; collybistin; gamma-Aminobutyric Acid; gephyrin; in vivo; kainate; molecular drug target; nervous system disorder; neuroligin 2; neurotransmitter release; new therapeutic target; novel; receptor; receptor function; transmission process

The activation of neurotransmitter receptors at synapses mediate synaptic transmission upon being bound by neurotransmitters released from presynaptic terminals. The predominant inhibitory transmitter in the brain is gamma-aminobutyric acid (GABA), and ionotropic GABAA receptors localize at inhibitory synapses to mediate fast inhibitory transmission. Dysregulation of GABA receptors causes various mental and neurological disorders including autism spectrum disorder, schizophrenia, epilepsy, and other disorders. However, precise mechanisms for synaptic localization of GABAA receptors remain unclear. We have recently identified novel GARLH family proteins as a critical regulator of synaptic GABAARs. In this proposal, we aim to reveal in vivo roles of GARLHs in regulating GABAAR activity in the brain, principle rules of GARLH-GABAAR interactions, and molecular relationships of constituents of inhibitory synapses. Successful completion of this proposed work will reveal fundamental molecular mechanisms for determining synaptic localization and transmission of GABAA receptors in the brain. Elucidating the molecular rules governing inhibitory transmission will enable us to identify putative molecular targets for drugs that may alleviate impair neurological and mental disorders.

突触上神经递质受体的激活介导突触传递 当被突触前终末释放的神经递质结合时。这个 大脑中主要的抑制性递质是伽马氨基丁酸(GABA)，以及 离子型GABA受体定位于抑制性突触，介导快速抑制性 变速箱。GABA受体调节失调导致多种精神和神经疾病 包括自闭症谱系障碍、精神分裂症、癫痫等 精神错乱。然而，GABAA受体突触定位的精确机制 目前仍不清楚。我们最近发现新的GARLH家族蛋白是一个关键的 突触GABA受体的调节者。在这项提案中，我们的目标是揭示在体内的作用 GARLHs对脑内GABAAR活性的调节，GARLH-GABAAR的基本规律 抑制性突触成分的相互作用和分子关系。 这项拟议工作的成功完成将揭示基本的分子 确定GABAA受体突触定位和传递的机制 在大脑里。阐明控制抑制传递的分子规则将使 美国将为可能减轻神经损伤的药物确定可能的分子靶点 和精神障碍。