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The Journal of Neuroscience, February 11, 2004, 24(6):1478-1485; doi:10.1523/JNEUROSCI.4734-03.2004
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Neurobiology of Disease
Dysregulation in the Suicide Brain: mRNA Expression of Corticotropin-Releasing Hormone Receptors and GABAA Receptor Subunits in Frontal Cortical Brain Region
Zul Merali,1,2
Lisheng Du,1
Pavel Hrdina,1
Miklos Palkovits,3
Gabor Faludi,4
Michael O. Poulter,5 and
Hymie Anisman1,5
1University of Ottawa Institute of Mental Health Research, and 2Departments of Psychology, Psychiatry, and Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario K1N 6N5, Canada, 3Laboratory for Neuromorphology, Hungarian Academy of Sciences and Semmelweis University, 1094 Budapest, Hungary, 4Semmelweis University Hospital, 1125 Budapest, Hungary, and 5Institute of Neuroscience, Carleton University, Ottawa, Ontario, K1S 5B6 Canada
Corticotropin-releasing hormone (CRH) and GABA have been implicated in depression, and there is reason to believe that GABA may influence CRH functioning. The levels of CRH, and mRNA for CRH-binding protein, CRH1, and CRH2 receptors, as well as various GABAA receptor subunits ( 1, 2, 3, 4, 5,  , and  2), were determined in several frontal cortical brain regions of depressed suicide victims and nondepressed individuals who had not died by suicide. Relative to the comparison group, CRH levels were elevated in frontopolar and dorsomedial prefrontal cortex, but not in the ventrolateral prefrontal cortex of suicide victims. Conversely, using quantitative PCR analyses, it was observed that, in frontopolar cortex, mRNA for CRH1, but not CRH2, receptors were reduced in suicide brains, possibly secondary to the high levels of CRH activity. In addition, mRNA of the 1, 3, 4, and receptor subunits was reduced in the frontopolar region of suicide victims. Interestingly, a partial analysis of the GABAA receptor functional genome revealed high cross-correlations between subunit expression in cortical regions of nondepressed individuals, suggesting a high degree of coordinated gene regulation. However, in suicide brains, this regulation was perturbed, independent of overall subunit abundance. These findings raise the possibility that the CRH and GABAA receptor subunit changes, or the disturbed coordination between these GABAA receptor subunits, contribute to depression and/or suicidality or are secondary to the illness/distress associated with it.
Key words: cortex; CRF; depression; GABA; prefrontal; human suicide; QPCR
Received Oct 20, 2003;
revised December 15, 2003;
accepted December 15, 2003.
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