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

D. Weissmann (1, 2) , S. van Der Laan (3) , D Underwood , N. Salvetat (2) , L. Cavarec (4) , L. Vincent , F. Molina (2) , M Mann , V Arango , F Pujol

1 Alcediag
2 Sys2Diag - Sys2Diag-Modélisation et Ingénierie des Systèmes Complexes Biologiques pour le Diagnostic
3 IGH - Institut de génétique humaine
4 Genomic Vision [Paris]

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.

Domaines: Sciences du Vivant [q-bio]

D. Weissmann, S. van Der Laan, D Underwood, N. Salvetat, L. Cavarec, et al.. Region-specific alterations of A-to-I RNA editing of serotonin 2c receptor in the cortex of suicides with major depression. Translational Psychiatry, 2016, 6 (8), pp.e878-e878. ⟨10.1038/tp.2016.121⟩. ⟨hal-02236898⟩