Identification of genes that regulate electrical synapse formation in vivo

Fred Hutchinson Cancer Research Center, Seattle WA

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Abstract

DESCRIPTION (provided by applicant): The long-term goal of this project is to understand the molecular pathways that regulate neural circuit and electrical synapse formation in vivo. Neural circuits are organized by synapses, which are specialized sites of adhesion and communication whose patterns and properties form the basis of all of brain function. Synapses can be either chemical, where signals are transmitted via neurotransmitter release and reception, or electrical, where signals pass directly through gap junctions between neurons. Of these, the chemical synapse has received more attention in recent years, however growing evidence suggests that electrical synapses are widespread in the brain where they modulate neural processing from vision to memory and learning. Underlying neural circuit and synapse formation are genetic mechanisms ensuring that neurons select appropriate targets and recruit the complex synaptic machinery to the sites of contact. However, the genes that regulate these processes are not well understood, especially in regard to electrical synapse formation. We propose to establish the zebrafish Mauthner (M) circuit as a model for understanding the genetic basis of neuronal target selection and electrical synapse formation. The well-characterized M circuit is simple and accessible, and is necessary for a stereotypical escape response behavior. These properties, in conjunction with genetic tools that specifically mark the cells of the neural circuit and their stereotyped chemical and electrical synapses, provide a unique opportunity to find mutations that affect electrical synaptogenesis, to understand the cellular basis of these defects, and to assess their behavioral consequences. The goal is to demonstrate that mutations affecting M electrical synapse formation can be identified using a forward genetic screen (Aim1), to demonstrate that these mutations specifically affect electrical synapse formation at the cell- biological level (Aim2) and that they have functional deficits that are evident at the level of the M-mediated escape response (Aim3). Overall this proposal will evaluate whether the M circuit is a suitable platform for studying vertebrate CNS electrical synapse formation; this will lay the groundwork for unraveling the underlying cellular and molecular mechanisms. Such knowledge is critical given that defects in synapse development or function are associated with a number of neurodevelopmental disorders, including autism and epilepsy, and also age-related diseases, such as Alzheimer<s. A fundamental understanding of how synapses are built is essential for improved detection of neurological disease and for guiding the development of therapies.