Group I (Gp1) metabotropic glutamate receptors, mGlu1 and mGlu5, are G protein-coupled receptors critical to formation and maintenance of brain circuitry and synaptic plasticity, a cellular substrate of learning and memory. Dysregulation of Gp1 mGluR activity is implicated in neurodevelopmental disorders including autism spectrum disorders and Fragile X syndrome. The broad spectrum of deficits linked to Gp1 mGluR dysfunctions is not adequately explained by existing knowledge on receptor properties. We identified a new mGlu1-binding protein, the adaptor protein fasciculation and elongation protein zeta-1 (FEZ1) that links mGlu1 to the autophagy initiation machinery. Preliminary findings indicate that mGlu1 may function via FEZ1 to inhibit autophagy in neurons. Autophagy is an evolutionarily conserved catabolic process critical to neuronal homeostasis and brain development. The proposed studies build on this progress to elucidate a fundamentally new mechanism by which Gp1 mGluRs can contribute to regulation of neuronal homeostasis. The requested Diversity Supplement will support Francisco J. Rivera-Rosario, a promising PhD student from an underrepresented group in Biomedical Research (Hispanic/Latino). The scope of the student's project and anticipated contributions are directly related to Aims 2 and 4 of the parent grant. Francisco will examine the contribution of a new mGlu1-interacting protein, Dip2b, in mediating Gp1 mGluR-dependent signaling to mTORC1 and dendritic spines structural plasticity. The project is tailored to provide training in state-of-the-art molecular and cellular techniques aligned with the student's interests. As part of the training the student will apply for an independent NRSA fellowship. Achieving these goals will contribute towards the grant aims and place the student in the position to fulfill his career goal of becoming an independent scientist.
Group I metabotropic glutamate receptors (mGluRs) are critical to formation and maintenance of brain circuitry, learning and memory. Abnormal mGluR activity is implicated in neuropsychiatric disorders including Fragile X syndrome, autism and schizophrenia. The aim of this proposal is to define the mechanisms by which mGluRs regulate autophagy and the impact of autophagy on receptor function in the brain.
