Understanding the Molecular Mechanisms that Maintain Excitation-Inhibition Balance in Neural Circuits

Neural circuit function is essential for healthy brain function. Disruption of synaptic connections is associated with multiple neurological disorders. The regulation of synapses by intrinsic mechanisms that act within neurons has provided extensive insight into the formation, function, and maintenance of synapses. Extrinsic mechanisms from both non-neuronal and systems-level sources also play a role in regulating synapses; however, these mechanisms are not completely understood. The goal of this project is to elucidate how multicellular interactions underlie the extrinsic mechanisms that modulate synaptic connectivity. By understanding how synapses are regulated by non-neuronal and systems-level interactions, this project will provide further insight for the treatment or management of neurological disorders such as epilepsy, autism, or neurodegenerative diseases. Caenorhabditis elegans (C. elegans) has been chosen as the model organism for this project for the following reasons: 1) it has been widely used for the study of synapse formation and function, 2) its synaptic connections have been completely mapped, 3) it retains the functional complexity of larger model systems in a reduced number of cells and intercellular connections, and 4) it is amenable to rapid genetic engineering, pharmacologic and optogenetic manipulations, and direct behavioral observations. Since many genes and signaling pathways are conserved from C. elegans to humans, C. elegans provides an excellent tool to study the molecular mechanisms associated with neurological disorders. The goals of this proposal will be accomplished through the following aims: Aim 1: Determine how epidermal-neuronal interactions are established and maintained by membrane-associated guanylate kinases. Aim 2: Determine how cytoskeletal adaptor proteins regulate phagocytosis of synapses. Aim 3: Determine how a new vesicular transporter modulates multiple neurotransmitters to regulate neural circuits. The completion of these aims will provide a deeper understanding of how synapses are regulated by extrinsic signaling mechanisms. Overall, this project will uncover new mechanisms that modulate neural circuit function and will provide novel therapeutic targets to prevent or ameliorate neurological disorders.