Abnormal maturation of brain circuitry during development is a critical determinant of pathological manifestations in neuropsychiatric conditions including intellectual disability, Fragile X syndrome and schizophrenia. A growing body of evidence from studies in human subjects and animal models has established a link between dysfunctions in glutamatergic neurotransmission and developmental brain abnormalities associated with these conditions. Group I 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 group I mGluR activity is implicated in neurodevelopmental disorders including Fragile X syndrome and schizophrenia. The broad spectrum of deficits linked to group I mGluR dysfunctions is not adequately explained by existing knowledge of receptor properties. We identified a new mGlu1-interacting protein, fasciculation and elongation protein zeta-1 (FEZ1) encoded by a schizophrenia candidate gene. Preliminary findings indicate that mGlu1 may function via FEZ1 to regulate 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 group I mGluRs can contribute to regulation of neuronal homeostasis under physiopathological conditions. We propose to 1) determine the cellular mechanisms by which group I mGluRs regulate autophagy in neurons; 2) define the molecular pathways by which the receptors control autophagy initiation; 3) establish whether constitutively enhanced group I mGluR activity leads to autophagy impairment in an animal model of Fragile X syndrome; and 4) investigate the function of autophagy in group I mGluR-dependent remodeling of dendritic spines. Collectively, findings from these studies will significantly advance our understanding of the molecular and cellular substrates underlying metabotropic functions in the brain and build a molecular framework to understand cellular perturbations associated with synaptic pathologies in neurodevelopmental disorders.
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.
