Evaluation of the protection against oxidative stress mediated by mitochondrial dysfunction and the behavioral properties of a derivative of vitamin E

I. A. KERMAN; R. BERNARD; R. C. THOMPSON; S. BURKE; I. AMREIN; F. MENG; S. J. EVANS; R. M. MYERS; E. G. JONES; W. E. BUNNEY; J. D. BARCHAS; A. F. SCHATZBERG; H. AKIL; S. J. WATSON
Society for Neuroscience. 2006.

Abstract

The brain serotonergic system has been implicated in the pathophysiology of mood disorders. To further understand the role of the dorsal raphe, a major source of serotonergic innervation of the forebrain, in the etiology of mood disorders we have used Affymetrix high density oligonucleotide microarrays to study gene expression profiles within this nucleus. Using in situ hybridization-guided laser capture microdissection we collected dorsal raphe samples from post-mortem brains of 6 patients diagnosed with bipolar disorder (BP), 13 patients with major depression (MD) and 9 control subjects (C). All subjects met inclusion criteria of brain pH > 6.6 and zero agonal factors. Total RNA was extracted and reverse transcribed, and after two rounds of amplification aRNA was hybridized to microarrays. Data were analyzed using robust multichip average (RMA) and percent present calls were calculated using ┬┐mas5calls┬┐ algorithm; significance values were calculated using ANOVA. Genes that showed a trend toward a significant change (p = 0.1) and were present in at least 50% of C, MD or BP subjects were analyzed using Ingenuity Pathway Analysis. The top networks that were affected in BP and MD included those of two common growth factors families and their downstream signaling molecules. Further analysis revealed 135 common genes that were significantly altered in both MD and BP. All of the common genes were altered in the same direction in both disorders. These findings suggest common mechanisms in the pathophysiology MD and BP, which involve different growth factor families. Expression validation using real-time polymerase chain reaction will be described for a subset of novel candidates. The authors are members of a research consortium supported by the Pritzker Neuropsychiatric Disorders Research Fund L.L.C. An agreement exists between the Fund and the universities involved to encourage the development of appropriate findings for research and clinical applications.