Delineating the synapse coordination pathway

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PROJECT SUMMARY All of brain function, from sensory perception to behavior, is derived from the pattern and properties of synaptic connections found between billions of individual neurons. These synapses are found in diverse forms, but two major classes exist: electrical and chemical synapses. While these classes are thought to be distinct biochemical units, it is clear the development of both types is linked. For example, the disruption of electrical synapses alters chemical synapse development resulting in a variety of behavioral defects, while perturbing chemical synapses impacts electrical synapse form and function. A barrier in the field remains in understanding how neurons coordinate the development of these distinct synapse types. Strikingly, emerging evidence suggests that such synaptic coordination may be achieved by a concerted regulatory pathway. Our work identifies the autism- and epilepsy-linked gene Neurobeachin as required for both electrical and chemical synapse formation by binding the intracellular scaffolds of both types of synapses, which are necessary for building functional synapses. Additionally, our preliminary work reveals that the disruption of Neurobeachin- interacting molecules also results in defects in both electrical and chemical synapse formation. These pieces of evidence begin to build a model wherein synapse coordination is achieved by a regulatory pathway that is essential for both synapse types. Yet, a critical gap remains in understanding the full extent of the genetic regulatory network that constitutes the synapse coordination pathway. Therefore, the goal of this project is to identify the genes that regulate electrical and chemical synapse coordination in vivo using a genetically accessible vertebrate model system. This proposal uses the zebrafish Mauthner circuit with its stereotyped electrical and chemical synapses and unparalleled genetic and imaging accessibility to assess synaptic coordination in vertebrates in vivo. In Aim1 we propose to identify candidate genes that coordinate electrical and chemical synapse formation using our efficient CRISPR screening pipeline. In Aim2 we examine the effects of candidate mutations on the formation and function of electrical and chemical synapses. Together, the proposed studies will identify the genes required to coordinate electrical and chemical synapse formation in vivo. This work has the potential to reveal a novel frontier in neuroscience, a pathway that coordinates electrical and chemical synapse development.