This is an application for a competing continuation of a grant line focused on receptor-based abnormalities in postmortem brain in schizophrenia. While we and others have published findings of abnormal glutamate receptor expression in the brain in schizophrenia, many findings have been subtle and often contradictory. These conflicting studies on the expression of NMDA and AMPA receptors led us in the last period of this grant and project to reconsider the """"""""glutamate hypothesis of schizophrenia"""""""" not as """"""""too many"""""""" or """"""""too few"""""""" receptors, but rather one of alterations in the cell biological processes that manage the total pool of receptors. We hypothesized that there are abnormalities of ionotropic glutamate receptor trafficking, delivery, dendritic localization, recycling, and degradation in schizophrenia. Our overarching hypothesis was that there are changes in NMDA and AMPARs in the brain in schizophrenia that involve abnormalities of specific intracellular processes. The data we have generated from postmortem frontal cortex samples in schizophrenia over the past 5 years support this model, with evidence for accelerated exit from the endoplasmic reticulum (ER) and Golgi apparatus of AMPA and NMDAR complexes including changes in N-linked glycosylation and expression of ER exit and retention signals, abnormal forward trafficking of these receptors, and changes in endosomal content of the AMPA receptors at the dendritic spine. Taken together, these abnormalities are consistent with diminished NMDA and/or AMPAR function even though total cellular levels of these receptors appears to be normal. We hypothesize, based on our prior work, that a fundamental defect in these brains is abnormal handling of the ionotropic receptor complex at the postsynaptic density in the synapse, and the evidence for forward trafficking is homeostatically driven within the cell to overcome this deficiency. We propose in this application, using postmortem brain samples from persons with schizophrenia and a comparison group, to determine the specificity of our findings to the NMDA and AMPARs as well as to the frontal cortex;to determine the extent of abnormality of N-linked and O-linked glycosylation of key proteins associated with glutamatergic neurotransmission;to examine intracellular proteins and posttranslational modifications associated with trafficking and synaptic targeting;and directly examine expression of these receptors in the postsynaptic density and other perisynaptic compartments. These data will permit us to test our model of schizophrenia being associated with abnormality of glutamate receptor dynamics in the dendritic spine.
This project will identify abnormalities of glutamate receptor expression and regulation in the brain in schizophrenia. Identification of the molecular defects underlying schizophrenia will provide new leads for the development of medicines to treat this illness.
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