Subcellular Glutamate Defects in Schizophrenia

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DESCRIPTION (provided by applicant): This project is designed to examine the expression, subcellular localization and posttranslational modifications of NMDA and AMPA glutamate receptor subunits and interacting proteins in autopsy-obtained brain tissue from patients with schizophrenia and a comparison group. Converging lines of evidence indicate that there are region specific changes in glutamate receptor transcript and protein expression in this illness. The glutamate hypothesis of schizophrenia is supported by pharmacological evidence suggesting involvement of glutamate receptor-signaling complexes, which includes glutamate receptor interacting proteins that are critical for normal NMDA and AMPA receptor assembly, trafficking, insertion in and removal from the plasma membrane, activation, and degradation. Previously, studies from our lab and others have detailed changes in glutamate receptor expression in schizophrenia. However, with a few exceptions, these data are inconsistent at best, and in some cases there is divergent polarity of changes in mRNA and protein levels. One possible explanation for these seemingly disparate results is that glutamatergic abnormalities in schizophrenia may include alterations in glutamate receptor trafficking, a notion consistent with studies that find alterations in glutamate receptor stoichiometry but not in the total number of receptors. Supporting this hypothesis, we have found robust and consistent changes in the expression of mRNA and protein for members of a family of intracellular AMPA and NMDA receptor interacting proteins in schizophrenia. We hypothesize that glutamatergic abnormalities in the schizophrenic brain include alterations in endoplasmic reticulum exit/retention, trafficking, delivery, dendritic localization and recycling/degradation of NMDA or AMPA receptors. Accordingly, we propose to perform transcript and protein analyses of novel molecules associated with synthesis, assembly, transport and localization of these receptors; co-immunoprecipitation studies of receptor subunits with known chaperone proteins critical for these cellular processes; protein measures of posttranslationally modified subunits and associated proteins, including phosphorylation, glycosylation, and ubiquitination; and protein assays in subcellular fractions from cortical tissue. These studies will comprehensively evaluate molecular and cellular events associated with NMDA and AMPA glutamate receptor synthesis, trafficking, recycling, and degradation in schizophrenia, highlighting abnormalities that can be targeted for the generation of novel treatment modalities for this disabling illness.