MOLECULAR BIOLOGY OF SYNAPTIC GROWTH AND PLASTICITY

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DESCRIPTION (Adapted from applicant's abstract): Two mechanisms (one activity-dependent, and the other activity-independent) are thought to regulate synaptic size and strength, and to function in parallel to expand the nerve terminal and its output to match the size of its target. Both mechanisms are proposed to depend on back and forth signaling between the pre- and postsynaptic cells. This study aims to identify new proteins that control synaptic growth, and to ask fundamental questions about the relationship between the structural and functional development of the synapse: How does the postsynaptic cell signal its size and activity to the presynaptic cell? By what means does the presynaptic cell respond? What is the relation between the growth of new synaptic release sites and the establishment of their function? Does development include the long-term modulation of transmission efficacy at release sites, as has been proposed to explain plasticity in adult? These studies will focus on a model genetic system, the glutamatergic neuromuscular synapse in the fruitfully Drosophila. The compelling reasons to use this system are the ability to conduct mutant screens, the ease of making transgenic animals, and the ready accessibility of the organism at many developmental stages to microscopic and physiological study. We will develop new protein-based optical reporters that will to visualize synaptic morphology, synaptic activity and the assembly of the protein signaling of the synapse. Transgenic methods will be used to generate stable lines of animals expressing these optical reporters in appropriate cells. These reporters will be used to follow synapse development with non-invasive time-lapse imaging, enabling us to elucidate the relationship between synapse formation and functional signaling in wild- type animals, as well as in mutants of synapse formation. The reporter expressing animals will also be used in large-scale mutant screens for new genes that control synaptic growth. The genes identified in the screen will be cloned, molecularly described, and placed into pre- and postsynaptic molecular signaling pathways. Synaptic growth genes discovered in Drosophila are likely to be highly conserved, allowing us to discover the I fundamental molecular machinery of synaptic growth in the human brain.