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 在大脑区域内和跨大脑区域之间的神经元之间的通信对于适当的大脑功能至关重要。这 沟通是由神经元令人兴奋的介导的，神经元令人兴奋，该神经元受到神经元抑制。加巴人 在介导神经元抑制中起着至关重要的作用，加巴活动的失调一直是 在各种疾病中实施，包括自闭症，癫痫和精神分裂症。 GABAARS媒体抑制 突触传播通过两个不同的机制，分体和补品抑制作用。阶段抑制是 快速和局部在突触中，滋补抑制作用是持久的，并且在整个树突和细胞中蔓延 身体。 尽管阶段性和补品抑制在控制神经元令人兴奋中的重要性，但对 他们在体内的独特角色。这是由于难以消除一种类型的抑制而不影响另一种抑制作用。 介导阶段和补品抑制的GABAAR的亚基组成是高度冗余的。 Garlhs 是控制GABAAR的突触定位的辅助亚基，而不会影响其表面 表达。在本研究中，我旨在揭示体内阶段性和补品抑制作用的不同作用 利用细胞特异性的GARLH敲除鼠标，在没有阶段性的抑制作用的情况下，没有 补品抑制作用的改变。此外，我发现在 GABAARβ1/2/3的新型条件三重敲除小鼠。通过对比行为表现和 这两只敲除小鼠之间突触的细胞生物学，我将能够辨别阶段的特定作用 和运动行为以及突触电路的形成和稳定性的补品抑制作用。 该提案的成功完成将揭示突触和突触外gabaars的关键作用 神经元的突触结构和运动行为。它还将揭示负责 GABAARS在成人大脑中的突触定位。结合在一起，这些结果将在我们的 了解大脑中抑制性神经传递，并有助于确定运动的关键治疗靶标 疾病。