Mechanisms regulating the structural plasticity of active zone cytomatrices at synapses between cortical neurons

During postnatal development, neuronal circuits in the mammalian cortex are subject to a period of refinement during which sensory experience leads to the formation of additional synaptic contacts between neurons at the expense of already established synapses. While the role of postsynaptic structures in the generation and turnover of glutamatergic synapses between cortical neurons is well understood, relatively little is known about presynaptic mechanisms contributing to synapse formation and maintenance. The long-term goal of our research program is to characterize the role of presynaptic structural alterations in the synaptic reorganization of neuronal circuits during development and to elucidate the molecular mechanisms regulating presynaptic structural plasticity. In the next grant cycle, we will address the role of mammalian orthologues of SYD-1, a putative RhoGTPase Activating Protein (RhoGAP) characterized in C. elegans and Drosophila, in the assembly and plasticity of presynaptic specializations. Specifically, we will - investigate the spatiotemporal expression pattern and the subcellular localization of two SYD-1 orthologues we have cloned from rat brain- address whether shRNA-mediated presynaptic knockdown of SYD-1 expression in cultured hippocampal neurons affects synapse density- determine whether such a knockdown decreases the stability of immature synapses- investigate the functional mechanism of mammalian SYD-1 In the short-term, our research program will determine the role of mSYD-1 isoforms in the assembly and structural plasticity of cortical synapses. These efforts will contribute to our long-term goal to elucidate the important role of presynaptic mechanisms in the elimination and stabilization of cortical synapses.