Abstract
Brain region-specific abnormalities in serotonergic transmission appear to underlie suicidal behavior. Alterations of RNA editing on the serotonin receptor 2C (HTR2C) pre-mRNA in the brain of suicides produce transcripts that attenuate 5-HT2CR signaling by impairing intracellular G-protein coupling and subsequent intracellular signal transduction. In brain, the distribution of RNA-editing enzymes catalyzing deamination (A-to-I modification) shows regional variation, including within the cerebral cortex. We tested the hypothesis that altered pre-mRNA 5-HT2CR receptor editing in suicide is region-specific. To this end, we investigated the complete 5-HT2CR mRNA-editing profile in two architectonically distinct cortical areas involved in mood regulation and decision-making in a clinically well-characterized cohort of age- and sex-matched non-psychiatric drug-free controls and depressed suicides. By using an original biochemical detection method, that is, capillary electrophoresis single-stranded conformational polymorphism (CE-SSCP), we corroborated the 5-HT2CR mRNA-editing profile previously described in the dorsolateral prefrontal cortex (Brodmann area 9 (BA9)). Editing of 5-HT2CR mRNA displayed clear regional difference when comparing dorsolateral prefrontal cortex (BA9) and anterior cingulate cortex (BA24). Compared with non-psychiatric control individuals, alterations of editing levels of 5-HT2CR mRNA were detected in both cortical areas of depressed suicides. A marked increase in editing on 5-HT2CR was especially observed in the anterior cingulate cortex in suicides, implicating this cortical area in suicide risk. The results suggest that region-specific changes in RNA editing of 5-HT2CR mRNA and deficient receptor function likely contribute to the etiology of major depressive disorder or suicide.
Highlights
IntroductionAccording to a very recent report, over a million suicides are reported per year worldwide.[1] A main risk factor for suicide is a psychiatric illness.[2,3] Suicide is a complex multifactorial outcome and its biological basis remains insufficiently understood
Suicide and suicidal behavior are major public health concerns worldwide
Fluorescent PCR products obtained following the second amplification and corresponding to standard isoforms and samples were added to a mixture of ROX-labeled migration standards (MWG-BIOTECH, AG; 0.5 μl each) proportion of isoforms representing less than 0.5% of the 5-HT2CR mRNA did not exceed 5% and was found to be higher in Brodmann area 9 (BA9) (4.6%) compared with BA24 (2.4%; Supplementary Figures S6 and S7)
Summary
According to a very recent report, over a million suicides are reported per year worldwide.[1] A main risk factor for suicide is a psychiatric illness.[2,3] Suicide is a complex multifactorial outcome and its biological basis remains insufficiently understood. Neither a single gene nor a single signaling pathway may entirely account for the development of a complex disease, low serotonergic activity and brain regional abnormalities in serotonin neurotransmission have been proposed as biological traits related to suicidal behavior.[4] Among the serotonin receptor family, the serotonin 2C receptor (5-HT2CR) is of particular interest, as it has been associated with regulation of mood, appetite, sleep and sexual behavior.[5,6] The serotonin 2C receptor is heterogeneously distributed in the brain, and, aside from the choroid plexus, is more abundant in the hypothalamus, hippocampus, prefrontal cortex and in regions containing dopamine and serotonin-synthesizing neurons.[7] Very recently a study identified two polymorphisms located in, respectively, the ADAR2 (RNA deaminase acting on RNA) and HTR2C genes associated with suicidal attempts, linking genetic and epigenetic factors to elevated risk of suicide.[8]
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