Constructing inhibitory synapses

构建抑制性突触

• 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
• 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

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（»Y-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主要归因于GABAA受体的激活，这是 Cl〜渗透配体门控离子通道。这些受体也是几个临床上重要的目标 药物类别，包括苯二氮卓类药物，巴比妥类药物，神经类动物和全身麻醉药。 在一系列CNS病理中，已隐含了GABAA受体功能的修饰。这是 对于有效的突触传播至关重要的是，GABAA接收器被聚集并稳定在 突触后的突触前部位与突触前的GABA能末端相对。但是，基于的机制 这些受体在突触定位上的选择性积累和稳定仍然未知。 我们假设该合成GABAA受体与外突触受体群体相反 降低了横向迁移率并增强了表面稳定性，动态行为的这种差异是 由Gephyrin调节，Gephyrin是一种在抑制突触形成的蛋白质。我们将使用一个 细胞生物学和生化方法的结合，以执行三种独立但相关的特异性 目标： 特定目的1：WEWILL检验突触和突触外GABAA接收器的假设 横向迁移率不同。 特定目的2：WEWILL检验突触和突触外GABAA接收器的假设 不同的细胞表面系统。 特定目的3：我们将测试gephyrin调节GABAA受体迁移率和 抑制突触的细胞表面稳定性。 总之，我们的方法将对主要决定者有更透彻的了解 调节GABAA受体在突触部位的积累。这些研究的结果将具有 为这种新的治疗策略做出重大贡献的潜力 使疾病衰弱，作为癫痫，动画，成瘾，自闭症和智力低下。