The role of GABA signaling in nervous system formation and homeostasis

GABA 信号传导在神经系统形成和稳态中的作用

• 批准号: RGPIN-2021-03017
• 负责人: SAMARUT, ERIC
• 金额: $ 2.19万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=761475
• 关键词: role; GABA; signaling; nervous; system

The complexity and proper function of the nervous system relies on its precise wiring. How does the right neural cells develop and connect at the right moment, in right numbers and at the right place? Many trophic factors have been identified as playing a role in the establishment of a well-connected nervous system. Particularly, ?-aminobutyric acid (GABA) plays a multi-faceted role in neural differentiation, migration and connection. However, the underlying exact mechanisms by which GABA signaling regulates neurogenesis and synaptogenesis are not fully understood. Our research project aims at dissecting the role of GABA signaling on neural network formation and homeostasis in vivo using zebrafish. In the last decade, zebrafish has emerged as a leading model to investigate biological issues such as development and physiology, particularly to decipher basic developmental mechanisms of the central nervous system. We previously showed that disrupting GABA signaling, via GABA receptor knock-out, leads to a severe impairment of the inhibitory neuronal network formation in zebrafish. Moreover, using an unbiased transcriptomic approach, we identified some key pathways that are specifically altered upon GABA signaling disruption. Taking advantage of zebrafish as a model to study neurosciences, and capitalizing on the expertise and on the genetic tools we have developed, we now plan: (1) To dissect in depth the role played by GABA signaling on brain excitatory/inhibitory neuronal network formation and homeostasis. Particularly, we are interested in investigating the role played by GABA signaling on excitatory versus inhibitory neuronal network formation and wiring in vivo. (2) To understand the differential role of the different GABA receptor subunits on neurogenesis and synaptogenesis. Using multiple genetic models, we will infer specific roles to the different GABA receptor subunits in order to to better understand how GABA signaling regulates neurogenesis and/or synaptogenesis in vivo. (3) To unravel novel pathways by which GABA signaling is regulating nervous system development. Our previous transcriptomic data identified specific axon guidance cues that are not expressed correctly upon GABA signaling disruption. After unravelling novel pathway(s) by which GABA signaling regulates neurogenesis, we propose to confirm these findings through rescue experiments using pharmacological and genetic approaches. Understanding the molecular substratum of the nervous system development and homeostasis gives us a much better understanding of how complex tissues develop and function. In this research program, we take advantage of zebrafish as a model and employ sophisticated techniques that allows investigating key fundamental questions in a genuine in vivo context. Our program will bring novel insights understanding of the mechanisms involved in the nervous system formation and homeostasis in vertebrates.

神经系统的复杂性和正常功能依赖于其精确的布线。正确的神经细胞是如何在正确的时间、正确的数量和正确的位置发育和连接的？许多营养因子已被确定在建立良好连接的神经系统中发挥作用。尤其是，？-氨基丁酸（GABA）在神经分化、迁移和连接中起多方面的作用。然而，GABA信号调节神经发生和突触发生的潜在确切机制尚未完全了解。我们的研究项目旨在解剖GABA信号在斑马鱼体内神经网络形成和稳态中的作用。在过去的十年中，斑马鱼已经成为研究发育和生理学等生物学问题的主要模型，特别是破译中枢神经系统的基本发育机制。 我们以前表明，破坏GABA信号，通过GABA受体敲除，导致严重损害斑马鱼的抑制性神经元网络的形成。此外，使用无偏见的转录组学方法，我们确定了一些关键的途径，特别是改变GABA信号中断。以斑马鱼为模型研究神经科学，并利用我们开发的专业知识和遗传工具，我们现在计划：（1）深入剖析GABA信号在大脑兴奋/抑制神经元网络形成和稳态中的作用。特别是，我们感兴趣的是在体内兴奋性与抑制性神经元网络的形成和布线的GABA信号所发挥的作用进行调查。(2)了解不同GABA受体亚单位在神经发生和突触发生中的不同作用。使用多种遗传模型，我们将推断不同GABA受体亚基的特定作用，以便更好地理解GABA信号转导如何调节体内神经发生和/或突触发生。(3)揭示GABA信号调节神经系统发育的新途径。我们以前的转录组数据确定了特定的轴突导向线索，GABA信号中断后没有正确表达。在揭示了GABA信号调节神经发生的新途径后，我们建议通过使用药理学和遗传学方法的拯救实验来证实这些发现。了解神经系统发育和体内平衡的分子基础，使我们更好地了解复杂组织的发育和功能。在这项研究计划中，我们利用斑马鱼作为模型，并采用先进的技术，允许在真正的体内环境中调查关键的基本问题。我们的计划将带来新的见解，了解脊椎动物神经系统形成和稳态的机制。