The overall goal of this research program is to better understand the molecular mechanisms by which N-methyl-D-aspartate receptors (NMDARs) are regulated to modulate synapse development and synaptic plasticity, and how these processes might be disrupted in complex neuropsychiatric disorders such as schizophrenia. The applicant for this K08 Mentored Clinical Scientist Research Career Development Award, Dr. John Gray, is a psychiatrist and a postdoctoral fellow with Dr. Roger Nicoll at UCSF. Dr. Gray's long-term research goals are to lead an independent research laboratory in psychiatric neuroscience at an academic institution combining cellular, molecular, electrophysiological, and genetic approaches to study synapse function with the goal of understanding how disruptions of the normal mechanisms of synapse development might underlie the pathophysiology of major neuropsychiatric disorders. Though etiological mechanisms underlying schizophrenia remain largely unknown, a convergence of pharmacologic and genetic data implicates a dysregulation of NMDAR function. NMDARs play critical roles in neurodevelopment and synaptic plasticity and subtle changes in NMDAR functioning can have wide-ranging developmental and cognitive effects. Most forebrain NMDARs contain two GluN1 and two GluN2A or GluN2B subunits, with receptor trafficking and functional properties largely dictated by the GluN2 subunit composition. Until recently the dogma in the field was that NMDARs were relatively immobile fixed structures, though it is now apparent that there is a remarkable plasticity of synaptic NMDARs. Indeed, the expression, trafficking, synaptic localization and functioning of different NMDARs subtypes are under dynamic cellular control, though the mechanisms are poorly understood. In this research plan, the roles of GluN2 subunit C-terminal tails in NMDAR synaptic targeting, trafficking, and regulation will be systematically investigated using an innovative molecular replacement approach in which native NMDARs are removed and replaced by recombinant NMDAR subunits in individual neurons. By combining his training in molecular and cellular biology, receptor pharmacology, and synaptic electrophysiology, Dr. Gray will pursue additional training in biochemical and proteomic analysis to address the following specific aims: 1) to determine the role of GluN2B-S1480 phosphorylation in NMDAR trafficking;2) to determine the mechanism of GluN2A targeting to synapses;and 3) to determine the role of tyrosine phosphorylation in NMDAR trafficking and regulation. Successful completion of this proposal will identify novel trafficking mechanisms, new targeting motifs and new proteins important in NMDAR regulation and synaptic development and plasticity and will open new frontiers for the development of disease-modifying therapeutic approaches for schizophrenia and other neuropsychiatric disorders.
Though the underlying causes of schizophrenia are poorly understood, accumulating evidence has implicated abnormalities in the function of NMDA receptors which are important for the development and adaptability of neuronal connections. I propose to use an innovative approach to improve our understanding of how neurons precisely control and regulate the levels of NMDA receptors throughout development. A detailed understanding of the mechanisms regulating NMDA receptors in neurons will provide critical insights that may facilitate the development of novel, disease-modifying approaches for the treatment of schizophrenia.