GLUTAMATE SYNAPSE ABNORMALITIES IN SCHIZOPHRENIC CORTEX

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DESCRIPTION: (Adapted from applicant's abstract)This project is designed to examine the expression of proteins associated with glutamate neurotransmission in the prefrontal and cingulate cortex of autopsy-obtained brain tissue from schizophrenic patients and matched controls. Converging evidence indicates that there are abnormalities of glutamatergic neurotransmission in specific brain regions in schizophrenia. While pharmacological evidence suggests involvement of the NMDA receptor in this illness, other studies and theoretical considerations suggest that other molecules associated with glutamatergic transmission may be abnormal in schizophrenia. The investigators hypothesize that there are abnormalities in the expression of the genes associated with the glutamate synapse in the limbic neocortex in schizophrenia. Accordingly, this project will examine the expression of these molecules in postmortem brain samples from schizophrenics and controls. The investigators propose to examine the proteins associated with the glutamate synapse in a comprehensive fashion, by (1) examining the expression of receptors, transporters, and anchoring proteins critical for glutamatergic neurotransmission; and (2) determining their expression at multiple levels of gene expression and organization, by determining the expression of the mRNAs encoding each, as well as protein levels, and higher order levels of protein organization as reflected by specific binding sites. While some evidence has accumulated to support the concept of a disturbance in glutamatergic transmission in schizophrenia, most previous studies have been limited in scope, often focusing on a single molecule in a discrete region of the brain. The investigators propose to conduct a comprehensive examination of the glutamate synapse in schizophrenia, by examining the expression of each molecule at multiple levels of molecular genetic organization. Further, the investigators will do this in the same brains, allowing meaningful comparisons within a given brain. At the conclusion of this set of experiments, the investigators will have a clearer understanding of the molecular genetic expression of the proteins associated with the glutamate synapse in schizophrenia at multiple levels of gene expression. Examination of the expression of these proteins critical for neurotransmission at the limbic cortical glutamate synapse may highlight abnormalities which can be more profitably targeted for novel treatment of this disabling illness.