Revealing distinct mechanisms and functions of neuronal inhibition in vivo

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是必不可少的。这 交流是由神经元兴奋性介导的，而兴奋性受到神经元抑制的严格控制。伽巴尔 在调节神经元抑制方面起着至关重要的作用，GABAAR活性的失调一直是 与多种疾病有关，包括自闭症、癫痫和精神分裂症。GABA受体介导的抑制作用 突触传递通过两种不同的机制，即时相抑制和紧张性抑制。而阶段抑制是 强直抑制快速且局限于突触，持续存在并扩散到整个树突和细胞。 尸体。 尽管时相抑制和强直抑制在控制神经元兴奋性方面很重要，但人们对此知之甚少。 它们在体内的独特作用。这是因为很难消除一种抑制而不影响另一种。 调节相位和紧张性抑制的GABA受体的亚基组成是高度冗余的。加尔赫 是控制GABAARs突触定位的辅助亚基，而不影响其表面 表情。在目前的研究中，我的目标是通过以下方式揭示在体内时相抑制和紧张性抑制的不同作用 利用细胞特异性的GARLH基因敲除小鼠，其中阶段抑制已经被取消，而不是 紧张性抑制的改变。此外，我还发现，时相抑制和主音抑制都在 GABAARβ1/2/3条件性三重基因敲除小鼠 这两个基因敲除小鼠之间突触的细胞生物学，我将能够辨别阶段的具体作用 以及在运动行为和突触回路的形成和稳定方面的紧张性抑制。 这一提议的成功完成将揭示突触和突触外GABA受体在 神经元的突触结构和运动行为。它还将揭示新的分子对 GABA受体在成人脑中的突触定位。总而言之，这些结果将为我们的 了解大脑中抑制性神经传递，并帮助确定运动的关键治疗靶点 精神错乱。

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.