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

Transl Psychiatry. 2016 Aug 30;6(8):e878. doi: 10.1038/tp.2016.121.

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.

MeSH terms

  • Adolescent
  • Adult
  • Autopsy
  • Case-Control Studies
  • Cerebral Cortex / metabolism
  • Deamination / genetics
  • Depressive Disorder, Major / genetics*
  • Electrophoresis, Capillary
  • Female
  • Gyrus Cinguli / metabolism*
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Single-Stranded Conformational
  • Prefrontal Cortex / metabolism*
  • RNA Editing / genetics*
  • RNA, Messenger / metabolism*
  • Receptor, Serotonin, 5-HT2C / genetics*
  • Self-Injurious Behavior / genetics*
  • Suicide*
  • Young Adult

Substances

  • RNA, Messenger
  • Receptor, Serotonin, 5-HT2C