The role of GABA signaling in nervous system formation and homeostasis

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为在建立良好连接的神经系统中起作用。特别是,?-氨基丁酸（GABA）在神经分化、迁移和连接中起着多方面的作用。然而，GABA信号调节神经发生和突触发生的潜在确切机制尚不完全清楚。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生物问题，如发育和生理学，特别是破译中枢神经系统的基本发育机制的主要模型。我们之前的研究表明，通过敲除GABA受体来破坏GABA信号，会导致斑马鱼抑制性神经元网络形成的严重损害。此外，使用无偏倚的转录组学方法，我们确定了GABA信号中断时特异性改变的一些关键途径。利用斑马鱼作为研究神经科学的模型，并利用我们开发的专业知识和遗传工具，我们现在计划：(1)深入解剖GABA信号在脑兴奋/抑制性神经元网络形成和稳态中的作用。我们特别感兴趣的是研究GABA信号在体内兴奋性与抑制性神经元网络形成和连接中的作用。(2)了解不同GABA受体亚基在神经发生和突触发生中的差异作用。利用多种遗传模型，我们将推断不同GABA受体亚基的具体作用，以便更好地了解GABA信号如何调节体内神经发生和/或突触发生。(3)揭示GABA信号调控神经系统发育的新途径。我们之前的转录组学数据确定了在GABA信号中断时不正确表达的特定轴突引导线索。在揭示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救援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可以让我们更好地了解复杂组织的发育和功能。在这个研究项目中，我们利用斑马鱼作为模型，并采用复杂的技术，在真实的体内环境中研究关键的基本问题。我们的项目将为脊椎动物神经系统形成和体内平衡的机制带来新的见解。

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.