Project Summary

Takanori Hashimoto, M.D., Ph.D. (Young Investigator 2004) of University of Pittsburgh, notes that local inhibitory neurotransmission, mediated by y-aminobutyric acid (GABA), appears to be dysfunctional in the prefrontal cortex (PFC) of individuals with schizophrenia (SZ). The signaling mediated by brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, has been suggested to regulate the development and maturation of PV-containing GABA neurons and the expression of gultamic acid decarboxylase (GAD67) and PV. Interestingly, BDNF and TrkB mRNAs are down-regulated in the PFC of subjects with SZ in a manner correlated with the decreases in GAD67 and PV mRNA expression. Therefore, Dr. Hashimoto proposes two projects to examine the involvement of BDNF-TrkB signaling in the decreased expression of GABA markers in the PFC of subject with schizophrenia. He will evaluate the effect of a single nucleotide polymorphism (SNP) on the decreased PFC expression of GABA markers in SZ, as an SNP was found to impact intracellular trafficking and secretion of BDNF in a human bdnf gene, by combining genotyping and quantification of mRNA expression in postmortem brain tissues. He will also directly test the role of BDNF-TrkB signaling in the regulation GABA marker expression by analyzing the expression of GAD67 and PV mRNAs in the PFC of genetically engineered mice with decreased expression of BDNF or TrkB.

Program Area: SCHIZOPHRENIA/PSYCHOTIC DISORDERS\Schizophrenia

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