Featured Finding Figure
Dysfunction of inhibitory neurons in the prefrontal cortex (PFC) appears to contribute to cognitive deficits in subjects with schizophrenia. Recent studies show decreased expression of GABA-related genes such as the 67-kilodalton isoform of glutamate decarboxylase (GAD67) and parvalbumin (PV). We investigated the involvement of signaling mediated by brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase (TrkB) in producing the altered GABA-related gene expression in schizophrenia. Both BDNF and TrkB mRNA levels were significantly decreased in the PFC of the subjects with schizophrenia, and the correlation between the changes in TrkB and GAD67 mRNA levels was significantly stronger than that between the changes in BDNF and GAD67 mRNA levels. In order to determine if these correlations represented cause and effect, we investigated mice hypomorphic for TrkB (fBZ locus). The above figure depicts representative autoradiograms illustrating TrkB (A-C), GAD67 (D-F), and PV (G-I) mRNA expression in a wild type mouse (left panels), a mouse heterozygous for the fBZ locus (fBZ/+) (center panels), and a mouse homozygous for the fBZ locus (fBZ/fBZ) (right panels) in adulthood. The densities of hybridization signals are presented in a pseudocolor manner according to the calibration scales (right side) for each mRNA. Note that TrkB mRNA is expressed in proportion to the gene dose (A-C). GAD67 and PV mRNA expression levels are decreased in the PFC of the fBZ/fBZ mouse (F and I) where the expression of TrkB mRNA is remarkably decreased (C). Arrowheads in panels A-C indicate the quantified regions in the PFC (this applies to all sections from each mouse). The decrease in TrkB signaling appears to underlie the dysfunction of inhibitory neurons in the PFC of subjects with schizophrenia.
Hashimoto T, Bergen SE, Nguyen QL, Xu B, Monteggia LM, Pierri JN, Sun Z, Sampson AR, Lewis DA: Relation of brain-derived neurotrophic factor and its receptor trkB to altered inhibitory prefrontal circuitry in schizophrenia. J Neurosci 25: 372-383, 2005.

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David A. Lewis, M.D. | Department of Psychiatry | University of Pittsburgh
3811 O'Hara Street, Biomedical Science Tower W1654
Pittsburgh, Pennsylvania 15213-2593
Phone: (412) 624-3894 - Fax: (412) 624-9910