Constructing inhibitory synapses

构建抑制性突触

基本信息

批准号：
8145453
负责人：
Stephen J Moss
金额：
$ 7万
依托单位：
TUFTS UNIVERSITY BOSTON
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-03-15 至 2011-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8145453
关键词：
Address Agonist Aminobutyric Acids Anxiety Anxiety Disorders Appearance Autistic Disorder Barbiturates Behavior Benzodiazepines Binding Biochemical Brain Bungarotoxins Cell Surface Receptors Cell surface Cellular biology Complement Coupled Development Diffuse Disease Drug Delivery Systems Endocytosis Engineering Epilepsy Exhibits Figs - dietary Fluorescence Fluorescence Recovery After Photobleaching Gated Ion Channel General anesthetic drugs Half-Life Health Hippocampus (Brain)Image Individual Inhibitory Synapse Intracellular Transport Lateral Life Ligands Measures Mediation Membrane Mental Retardation Methodology Modeling Modification Nervous system structure Neurons Neurotransmitters PHluorin Pathology Pharmaceutical Preparations Plasmids Play Population Property Protein Synthesis Inhibitors Proteins RNA Interference Relative (related person)Reporter Role Site Sleep Disorders Structure Surface Synapses Synaptic Receptors Synaptic Transmission Testing Time addiction barbituric acid salt base cell motility extracellular gamma-Aminobutyric Acid gephyrin hypnotic insight knockout gene neurosteroids novel therapeutics postsynaptic presynaptic receptor receptor function research study residence sedative synaptic inhibition therapeutic target vector

项目摘要

GABA (¿y-aminobutyric acid) is the major inhibitory neurotransmitter in the mammalian nervous system. The fast synaptic inhibitory action of GABA is due largely to the activation of GABAA receptors, which are Cl~ permeable ligand-gated ion channels. These receptors are also targets for several clinically important drug classes, including benzodiazepines, barbiturates, neurosteroids and general anesthetics. Modifications of GABAA receptor function have been implicated in a range of CNS pathologies. It is essential for efficient synaptic transmission that GABAA receptors are clustered and stabilized at postsynaptic sites opposed to presynaptic GABAergic terminals. However, the mechanisms that underlie the selective accumulation and stabilization of these receptors at synaptic localizations remain unknown. We hypothesize that synaptic GABAA receptors, as opposed to extrasynaptic receptor populations, exhibit reduced lateral mobilities and enhance surface stabilities and that this difference in dynamic behavior is regulated by gephyrin, a protein implicated in the formation of inhibitory synapses. Thus we will use a combination of cell biology and biochemical approaches to carry out three independent but related specific aims: Specific Aim 1: Wewill test the hypothesis that synaptic and extrasynaptic GABAA receptors have different rates of lateral mobility. Specific Aim 2: Wewill test the hypothesis that synaptic and extrasynaptic GABAA receptors have different cell surface stabilities. Specific Aim 3: We will test the hypothesis that gephyrin regulates GABAA receptor mobility and cell surface stability at inhibitory synapses. Together, our approacheswill provide a more thorough understanding of the primary determinants that regulate accumulation of GABAA receptors at synaptic sites. The results of these studies will have the potential to make significant contributions to the development of novel therapeutic strategies for such debilitating disorders as epilepsy, anxiety,addiction, autism, and mental retardation.

GABA（γ-氨基丁酸）是哺乳动物神经系统中主要的抑制性神经递质。 GABA 的快速突触抑制作用很大程度上是由于 GABAA 受体的激活，这些受体是 Cl~ 可渗透的配体门控离子通道这些受体也是一些临床上重要的靶标。药物类别，包括苯二氮卓类药物、巴比妥类药物、神经类固醇和全身麻醉剂。 GABAA 受体功能的改变与一系列中枢神经系统病理有关。 GABAA 受体聚集并稳定在有效的突触传递所必需的然而，突触后位点与突触前 GABA 能末端相反，其机制如下。这些受体在突触定位的选择性积累和稳定仍然未知。我们认为，与突触外受体群体相反，突触 GABAA 受体表现出减少横向流动性并增强表面稳定性，并且这种动态行为的差异是受 gephyrin 调节，gephyrin 是一种与抑制性突触形成有关的蛋白质。结合细胞生物学和生化方法来进行三个独立但相关的特定目标：具体目标 1：我们将检验突触和突触外 GABAA 受体具有不同的横向移动率。具体目标 2：我们将检验突触和突触外 GABAA 受体具有不同的细胞表面统计数据。具体目标 3：我们将检验 gephyrin 调节 GABAA 受体迁移率的假设抑制性突触的细胞表面稳定性。总之，我们的方法将提供对主要决定因素的更透彻的理解。调节 GABAA 受体在突触位点的积累这些研究的结果将具有以下结果。有望为此类疾病的新型治疗策略的开发做出重大贡献使人衰弱的疾病，如癫痫、焦虑、成瘾、自闭症和智力低下。