Peptidergic Modulation of NMDA-Receptor Mediated Neurotransmission

Synapses control information processing by the nervous system, and dysfunction of synapses is associated with many neurological diseases and neurodegenerative disorders. In all nervous systems, glutamate is the primary excitatory neurotransmitter used to activate neurons. The goals of this study are to provide important, new mechanistic insights into the function of glutamatergic synapses, which will aid in our understanding of information processing by the brain and provide new avenues for the development of pharmaceutical therapies for nervous system disorders. Using a genetic platform based on the nervous system of the model organism C. elegans, we will study how peptide ligands, which signal via G-protein coupled receptors, regulate synaptic function mediated by NMDA-type ionotropic glutamate receptors (NMDARs). Synaptic NMDARs are involved in the pathophysiology of numerous psychiatric and neurological disorders. We propose an integrated multidisciplinary approach that combines in vivo electrophysiological analysis, behavioral studies and optogenetic to study the mechanism of action by which specific neuropeptides regulate NMDAR-mediated synaptic signaling. These studies have particular promise for a deeper understanding of nervous system plasticity, and behaviors such as learning and memory. Our studies will reveal new targets for the development of new drugs and novel therapeutic strategies for disorders of nervous system function.