Molecular Mechanisms Controlling Synaptic Function

Washington University, Saint Louis MO

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Abstract

DESCRIPTION (provided by applicant): The primary means by which most neurons communicate with their target cells is through the regulated release of neurotransmitter from synapses. Modulation of the release properties of these synapses has long been postulated, and in certain circumstances been directly demonstrated, to be a critical component of the cellular mechanisms that underlie learning and memory. A molecular understanding of the mechanisms that mediate this release process is crucial to developing a comprehensive understanding of brain function both in health and in disease. Over a decade of molecular studies of the presynaptic terminal has led to the identification of over one hundred gene products that are implicated in the release process at the presynaptic nerve terminal. Yet, the role of many of these proteins in regulating release still is unknown. Homologs of most of the molecules implicated in this process are present in the nematode Caenorhabditis elegans. Included among these conserved molecules are about a dozen proteins implicated in the function of rab3, a small synaptic vesicle-associated GTPase of the ras superfamily. Analysis of mutants lacking rab3 components in C. elegans and mouse have demonstrated a role for this pathway both in regulating basal transmitter release and in presynaptic-forms of synaptic plasticity. This proposal aims to utilize molecular genetic tools available for the study of C. elegans to further dissect the role of rab3 pathway constituents in synaptic function. Nematode mutants lacking four rab3 components have been previously isolated and characterized. Analysis of these mutants has revealed that some of these molecules play central roles in neuronal function, while others appear to be largely dispensable. Building upon this foundation of mutants previously isolated in C. elegans, we propose to isolate additional mutants lacking rab3 pathway components and to characterize the neuronal defects of animals lacking these molecules. Secondly, we propose several lines of experimentation aimed at dissecting the molecular mechanisms that govern how neurons localize a subset of these pathway components specifically at the nerve terminal. The ultimate aim is to integrate the role of the rab3 regulatory machinery seamlessly into a detailed description of the basic mechanisms that underlie the release of neurotransmitter from synaptic terminals.