MicroRNA Expression Is Down-Regulated and Reorganized in Prefrontal Cortex of Depressed Suicide Subjects
journal contributionposted on 2012-09-18, 00:00 authored by Neil R. Smalheiser, Giovanni Lugli, Hooriyah S. Rizavi, Vetle I. Torvik, Gustavo Turecki, Yogesh Dwivedi
BACKGROUND: Recent studies suggest that alterations in expression of genes, including those which regulate neural and structural plasticity, may be crucial in the pathogenesis of depression. MicroRNAs (miRNAs) are newly discovered regulators of gene expression that have recently been implicated in a variety of human diseases, including neuropsychiatric diseases. METHODOLOGY/PRINCIPAL FINDINGS: The present study was undertaken to examine whether the miRNA network is altered in the brain of depressed suicide subjects. Expression of miRNAs was measured in prefrontal cortex (Brodmann Area 9) of antidepressant-free depressed suicide (n = 18) and well-matched non-psychiatric control subjects (n = 17) using multiplex RT-PCR plates. We found that overall miRNA expression was significantly and globally down-regulated in prefrontal cortex of depressed suicide subjects. Using individual tests of statistical significance, 21 miRNAs were significantly decreased at p = 0.05 or better. Many of the down-regulated miRNAs were encoded at nearby chromosomal loci, shared motifs within the 5'-seeds, and shared putative mRNA targets, several of which have been implicated in depression. In addition, a set of 29 miRNAs, whose expression was not pairwise correlated in the normal controls, showed a high degree of co-regulation across individuals in the depressed suicide group. CONCLUSIONS/SIGNIFICANCE: The findings show widespread changes in miRNA expression that are likely to participate in pathogenesis of major depression and/or suicide. Further studies are needed to identify whether the miRNA changes lead to altered expression of prefrontal cortex mRNAs, either directly (by acting as miRNA targets) or indirectly (e.g., by affecting transcription factors)
This research was supported by grants from the National Institute of Mental Health (R21MH081099; R01 MH68777; R01 MH082802; R21MH091509), the American Foundation for Suicide Prevention, and the Stanley Medical Research Institute. The work was also partly supported by the FRSQ (Fonds de la recherche en sante´ du Que´bec) and Canadian Institute of Health Research MOP-190734 and MOP-171859. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher StatementThe original version is available through PLoS One at DOI:10.1371/journal.pone.0033201 © 2012 Smalheiser et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.