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The Journal of Neuroscience, November 28, 2007, 27(48):13329-13340; doi:10.1523/JNEUROSCI.4083-07.2007

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Neurobiology of Disease
Gene Expression Profiling in Postmortem Prefrontal Cortex of Major Depressive Disorder

Hyo Jung Kang,1 David H. Adams,1 Arthur Simen,1 Birgitte B. Simen,1 Grazyna Rajkowska,2 Craig A. Stockmeier,2,3 James C. Overholser,4 Herbert Y. Meltzer,5 George J. Jurjus,3 Lisa C. Konick,3 Samuel S. Newton,1 and Ronald S. Duman1

1Department Psychiatry, Yale University, New Haven, Connecticut 06508, 2Department Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, Mississippi 39216, Departments of 3Psychiatry and 4Psychology, Case Western Reserve University, Cleveland, Ohio 44106, and 5Psychiatric Hospital at Vanderbilt, Nashville, Tennessee 37212

Correspondence should be addressed to Ronald S. Duman, Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511. Email: ronald.duman{at}yale.edu

Investigations of the molecular mechanisms underlying major depressive disorder (MDD) have been hampered by the complexity of brain tissue and sensitivity of gene expression profiling approaches. To address these issues, we used discrete microdissections of postmortem dorsolateral prefrontal cortex (DLPFC) (area 9) and an oligonucleotide (60mer) microarray hybridization procedure that increases sensitivity without RNA amplification. Mixed-effects statistical methods were used to rigorously control for medication usage in the subset of medicated depressed subjects. These analyses yielded a rich profile of dysregulated genes. Two of the most highly dysregulated genes of interest were stresscopin, a neuropeptide involved in stress responses, and Forkhead box D3 (FOXD3), a transcription factor. Secondary cell-based analysis demonstrated that stresscopin and FoxD3 are increased in neurons of DLPFC gray matter of MDD subjects. These findings identify abnormal gene expression in a discrete region of MDD subjects and contribute to further elucidation of the molecular alterations of this complex mood disorder.

Key words: microarray; stresscopin; urocortin III; stress; corticotrophin releasing hormone; FoxD3; fibroblast growth factor

Received June 11, 2007; revised Oct. 15, 2007; accepted Oct. 16, 2007.

Correspondence should be addressed to Ronald S. Duman, Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511. Email: ronald.duman{at}yale.edu






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