The role of GABA signaling in nervous system formation and homeostasis

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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.