Region-specific alterations of A-to-I RNA editing of serotonin 2c receptor in the cortex of suicides with major depression

• Published in: Translational psychiatry 2016-08, Vol.6 (8), p.e878-e878
• Main Authors: Weissmann, D, van der Laan, S, Underwood, M D, Salvetat, N, Cavarec, L, Vincent, L, Molina, F, Mann, J J, Arango, V, Pujol, J F
• Format: Article
• Language: English
• Subjects: 38/77; 42/34; 45/29; 45/90; 692/53/2421; 692/699/476/1414; Adolescent; Adult; Autopsy; Behavioral Sciences; Biological Psychology; Case-Control Studies; Cerebral Cortex - metabolism; Deamination - genetics; Depressive Disorder, Major - genetics; Electrophoresis, Capillary; Female; Gyrus Cinguli - metabolism; Humans; Life Sciences; Male; Medicine; Medicine & Public Health; Middle Aged; Neurosciences; Original; original-article; Pharmacotherapy; Polymorphism, Single-Stranded Conformational; Prefrontal Cortex - metabolism; Psychiatry; Receptor, Serotonin, 5-HT2C - genetics; RNA Editing - genetics; RNA, Messenger - metabolism; Self-Injurious Behavior - genetics; Suicide; Young Adult
• ISSN: 2158-3188; 2158-3188
• DOI: 10.1038/tp.2016.121

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-HT 2C R 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-HT 2C R receptor editing in suicide is region-specific. To this end, we investigated the complete 5-HT 2C R 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-HT 2C R mRNA-editing profile previously described in the dorsolateral prefrontal cortex (Brodmann area 9 (BA9)). Editing of 5-HT 2C R 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-HT 2C R 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-HT 2C R mRNA and deficient receptor function likely contribute to the etiology of major depressive disorder or suicide.