Revealing distinct mechanisms and functions of neuronal inhibition in vivo

揭示体内神经元抑制的独特机制和功能

• 批准号: 10188373
• 负责人: Erika Hoyos-Ramirez
• 金额: $ 7.49万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10188373
• 关键词: Adult; Affect; Aging; Alzheimer' s Disease; Animal Behavior; Architecture; Behavioral; Binding; Brain; Brain region; Cell Adhesion Molecules; Cells; Cellular biology; Communication; Complex; Dendrites; Disease; Epilepsy; Equilibrium; Genetic; Hippocampus (Brain); Inhibitory Synapse; Ion Channel; Knockout Mice; Lead; Light; Mediating; Molecular Biology; Morphology; Motor; Multiple Sclerosis; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Pattern; Performance; Pharmacology; Phase; Phenotype; Play; Presynaptic Terminals; Property; Protein Family; Purkinje Cells; Pyramidal Cells; Reagent; Role; ST5 gene; Schizophrenia; Site; Spinocerebellar Ataxias; Surface; Synapses; Synaptic Transmission; Time; age related; age related neurodegeneration; autism spectrum disorder; behavioral study; cell behavior; gamma-Aminobutyric Acid; in vivo; insight; millisecond; mind control; motor behavior; motor disorder; mouse model; neural circuit; neuroligin 2; neuronal circuitry; neuronal excitability; neurotransmission; novel; postsynaptic; protein distribution; receptor; therapeutic target

Summary/Abstract Communication between neurons within and across brain regions is essential for proper brain function. This communication is mediated by neuronal excitability, which is tightly controlled by neuronal inhibition. GABAARs play an essential role in mediating neuronal inhibition, and dysregulation in GABAAR activity has been implicated in a variety of disorders, including autism, epilepsy and schizophrenia. GABAARs mediate inhibitory synaptic transmission through two distinct mechanisms, phasic and tonic inhibition. While phasic inhibition is fast and localized at synapses, tonic inhibition is persistent and spreads throughout the dendrite and the cell body. Despite the importance of phasic and tonic inhibition in controlling neuronal excitability, little is known about their distinct roles in vivo. This is due to difficulty in eliminating one type of inhibition without affecting the other. The subunit composition of the GABAARs that mediate phasic and tonic inhibition is highly redundant. GARLHs are auxiliary subunits that control the synaptic localization of GABAARs, without affecting their surface expression. In the present study, I aim to reveal the distinct roles of phasic and tonic inhibition in vivo by making use of a cell-specific GARLH knockout mouse, where phasic inhibition has been abolished without alterations in tonic inhibition. Furthermore, I have found that both phasic and tonic inhibition are abolished in a novel conditional triple knockout mice of GABAAR β1/2/3. By contrasting the behavioral performance and the cell biology of synapses between these two knockout mice, I will be able to discern the specific roles of phasic and tonic inhibition in motor behavior and in the formation and stability of synaptic circuits. Successful completion of this proposal will reveal critical roles for synaptic and extrasynaptic GABAARs in the synaptic architecture of neurons, and motor behavior. It will also reveal novel molecules responsible for the synaptic localization of GABAARs in the adult brain. Combined, these results will provide valuable insight in our understanding of inhibitory neurotransmission in the brain, and help identify key therapeutic targets for motor disorders.

摘要/摘要 大脑区域内和大脑区域之间的神经元之间的通信对于大脑的正常功能至关重要。 沟通是由神经元兴奋性介导的，而神经元兴奋性受到神经元抑制的严格控制。 GABAAR 活性的失调在介导神经元抑制中发挥重要作用 GABAAR 与多种疾病有关，包括自闭症、癫痫和精神分裂症。 突触传递通过两种不同的机制，即阶段性抑制和强直性抑制。 强直性抑制快速且集中于突触，持续存在并扩散到整个树突和细胞 身体。 尽管阶段性和强直性抑制在控制神经兴奋性方面很重要，但人们对它知之甚少。 它们在体内的作用不同，这是因为很难消除一种抑制而不影响另一种抑制。 介导阶段性和强直性抑制的 GABAAR 亚基组成是高度冗余的。 是控制 GABAAR 突触定位的辅助亚基，而不影响其表面 在本研究中，我的目的是揭示体内阶段性和强直性抑制的不同作用。 利用细胞特异性 GARLH 基因敲除小鼠，其中阶段性抑制已被废除，无需 此外，我发现相位抑制和强直抑制都被废除了。 通过比较行为表现和 GABAAR β1/2/3 的新型条件三重敲除小鼠。 通过这两只基因敲除小鼠之间突触的细胞生物学，我将能够辨别阶段性的具体作用 运动行为以及突触回路的形成和稳定性中的强直抑制。 该提案的成功完成将揭示突触和突触外 GABAAR 在 它还将揭示神经元突触结构和运动行为。 结合起来，这些结果将为我们提供有价值的见解。 了解大脑中的抑制性神经传递，并帮助确定运动神经传递的关键治疗靶点 失调。