Project Summary

Takanori Hashimoto, M.D., Ph.D. (Young Investigator 2006) of Western Psychiatric Institute and Clinic and the University of Pittsburgh , notes that in the dorsolateral prefrontal cortex (DLPFC) of individuals with schizophrenia, inhibitory neurotransmission -- mediated by γ-aminobutyric acid (GABA)--appears to be dysfunctional, as indicated by decreased expression of an enzyme for GABA synthesis, GAD67.This change appears to be selective for certain GABA neurons that express parvalbumin (PV), indicating attenuated GABA transmission by these neurons. These PV-neurons also exhibit decreased gene expression for GABA transporter 1 (GATl). Given the critical roles of PV-containing neurons in regulating the DLPFC circuitry, these alterations appear to underlie working memory deficits observed in schizophrenia. To better understand these alterations in PV-containing neurons in schizophrenia and to design effective therapeutic strategies, Dr. Hashimoto proposes two projects. First, he will test if the alterations in PV-containing neurons serve as a common mechanism for the functional abnormalities of different cortical regions in schizophrenia. He will evaluate the expression of a set of GABA-related genes, such as those encoding GAD67, GATl, and PV, in multiple cortical regions including the DLPFC, anterior cingulate cortex, and superior temporal gyrus. Second, he will test whether the decreased GATl and PV mRNA levels are secondary to the deficit in GAD67 expression. He will analyze cortical GABA-related gene expression in mice with a targeted disruption of the GAD67 gene.

Program Area: SCHIZOPHRENIA/PSYCHOTIC DISORDERS\Schizophrenia

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