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

基本信息

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
项目类别：
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

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

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项目摘要

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.

突触中神经递质受体的激活介导突触传播受到从突触前末端释放的神经递质束缚后。这大脑中主要的抑制性递质是γ-氨基丁酸（GABA）和离子型GABAA受体位于抑制性突触以介导快速抑制的抑制作用传播。 GABA受体的失调会引起各种心理和神经系统包括自闭症谱系障碍，精神分裂症，癫痫和其他疾病疾病。但是，GABAA受体突触定位的精确机制保持不清楚。我们最近将新颖的Garlh家族蛋白确定为关键突触Gabaars的调节器。在此提案中，我们旨在揭示体内角色 GARLHS在调节大脑中的Gabaar活动时，Garlh-Gabaar的主要规则相互作用和抑制突触成分的分子关系。成功完成这项建议的工作将揭示基本分子确定GABAA受体的突触定位和传播的机制在大脑中。阐明控制抑制传播的分子规则将实现我们确定可能减轻神经系统的药物的假定分子靶标和精神障碍。