The goal of this NRSA F30 application is to provide training in innovative techniques that will permit the applicant to advance his knowledge and skills in the field of translational mental health research. The applicant will test hypotheses involving the role of trafficking of the AMPA-subtype glutamate receptor in the pathophysiology of schizophrenia. To achieve this goal, the applicant will combine coursework, the proposed research project, as well as exposure to the diagnosis and treatment of severe mental illness in the clinic. This combination of translational experiences will allow the applicant to develop a successful career as a clinician investigator. The alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor complex is a critical part of glutamate transmission, and plays an important role in synaptic plasticity and executive function. Data gathered from numerous preclinical, clinical, experimental, and imaging studies have indicated alterations in AMPA receptor expression in schizophrenia. These findings indicate that changes in AMPA receptors in this illness are not simply a problem of too many or too few receptors, but a problem with the trafficking and localization of the receptors. Specifically, we hypothesize that there is a decrease in AMPA receptors localized to the synapse, and increased levels of AMPA receptors in endosomes, reflecting diminished stability of AMPA receptors in the post-synaptic density. We propose to isolate early, late, and recycling endosomes from dorsolateral prefrontal cortex and anterior cingulate cortex of subjects with schizophrenia and a comparison group. Using these fractions, we will examine AMPA subunit expression and post- translational modifications of the AMPA receptor subunits, including phosphorylation and glycosylation, as well as the expression of molecules that regulate AMPA trafficking. To assess for potential effects of antipsychotic treatment, we will assess our dependent measures in endosomes isolated from rats treated with antipsychotic medication. Our proposed studies will lead to a better understanding of the importance of endosomes in the trafficking of AMPA receptor from the synapse and may identify novel deficits involved in the pathophysiology of schizophrenia, leading to new diagnostic and treatment strategies. Schizophrenia is a serious mental illness that affects approximately 1% of the population. Accumulating evidence implicates glutamate receptors in schizophrenia. This project will examine glutamate receptor trafficking in this illness, ultimately leading to better diagnostic and treatment strategies.
|Hammond, John C; McCullumsmith, Robert E; Haroutunian, Vahram et al. (2011) Endosomal trafficking of AMPA receptors in frontal cortex of elderly patients with schizophrenia. Schizophr Res 130:260-5|
|Hammond, John C; McCullumsmith, Robert E; Funk, Adam J et al. (2010) Evidence for abnormal forward trafficking of AMPA receptors in frontal cortex of elderly patients with schizophrenia. Neuropsychopharmacology 35:2110-9|