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BIOLOGICAL SCIENCES / MEDICAL SCIENCES
Regulation of the GABA cell phenotype in hippocampus of schizophrenics and bipolars

Francine M. Benes^*,,, Benjamin Lim, David Matzilevich, John P. Walsh, Sivan Subburaju, and Martin Minns

*Program in Structural and Molecular Neuroscience, McLean Hospital, Belmont, MA 02178; and Program in Neuroscience and Department of Psychiatry, Harvard Medical School, Boston, MA 02110

Communicated by Erminio Costa, University of Illinois, Chicago, IL, April 25, 2007 (received for review March 19, 2007)

GABAergic dysfunction is present in the hippocampus in schizophrenia (SZ) and bipolar disorder (BD). The trisynaptic pathway was "deconstructed" into various layers of sectors CA3/2 and CA1 and gene expression profiling performed. Network association analysis was used to uncover genes that may be related to regulation of glutamate decarboxylase 67 (GAD₆₇), a marker for this system that has been found by many studies to show decreased expression in SZs and BDs. The most striking change was a down-regulation of GAD₆₇ in the stratum oriens (SO) of CA2/3 in both groups; CA1 only showed changes in the SO of schizophrenics. The network generated for GAD₆₇ contained 25 genes involved in the regulation of kainate receptors, TGF- and Wnt signaling, as well as transcription factors involved in cell growth and differentiation. In SZs, IL-1, (GRIK2/3), TGF-2, TGF-R1, histone deacetylase 1 (HDAC1), death associated protein (DAXX), and cyclin D2 (CCND2) were all significantly up-regulated, whereas in BDs, PAX5, Runx2, LEF1, TLE1, and CCND2 were significantly down-regulated. In the SO of CA1 of BDs, where GAD67 showed no expression change, TGF- and Wnt signaling genes were all up-regulated, but other transcription factors showed no change in expression. In other layers/sectors, BDs showed no expression changes in these GAD₆₇ network genes. Overall, these results are consistent with the hypothesis that decreased expression of GAD₆₇ may be associated with an epigenetic mechanism in SZ. In BD, however, a suppression of transcription factors involved in cell differentiation may contribute to GABA dysfunction.

epigenetics | network association analysis | PAX5 | Runx2 | HDAC1

Author contributions: F.M.B. designed research; F.M.B., B.L., D.M., and J.P.W. performed research; F.M.B. contributed reagents/analytic tools; F.M.B., B.L., and M.M. analyzed data; and F.M.B. and S.S. wrote the paper.

The authors declare no conflict of interest.

This article contains supporting information online at www.pnas.org/cgi/content/full/0703806104/DC1.

To whom correspondence should be addressed. E-mail: fbenes{at}mclean.harvard.edu

© 2007 by The National Academy of Sciences of the USA

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