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Increased serotonin 2C receptor mRNA editing: a possible risk factor for suicide

Abstract

Suicide is a major public health problem with 1 million victims each year worldwide. Up to 90% of adults who commit suicide have at least one psychiatric diagnosis such as major depression, bipolar disorder (BPD), schizophrenia (SZ), substance abuse or dependence. A question that has remained unanswered is whether the biological substrates of suicide are distinct from those of the psychiatric disorders in which it occurs. The serotonin 2C receptor (5-HT2CR) has been implicated in depression and suicide. We, therefore, compared the frequencies of its mRNA editing variants in postmortem prefrontal cortical specimens from subjects who committed suicide or who died from other causes. All suicides occurred in the context of either SZ or BPD. The non-suicide cases included subjects with either SZ or BPD as well as subjects with no psychiatric diagnosis. We identified 5-HT2CR mRNA editing variations that were associated with suicide but not with the comorbid psychiatric diagnoses, and were not influenced by demographic characteristics (age and sex) and alcohol or drug use. These variations consisted of a significant increase in the pool of mRNA variants (ACD and ABCD) that encode one of the most prevalent and highly edited isoforms of 5-HT2CR, that is, VSV (Val156–Ser158–Val160). Because the VSV isoform of 5-HT2CR exhibits low functional activity, an increase in its expression frequency may significantly influence the serotonergic regulation of the brain. Thus, at least in patients with SZ or BPD, overexpression of the VSV isoform in the prefrontal cortex may represent an additional risk factor for suicidal behavior.

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References

  1. McGuffin P, Marusic A, Farmer A . What can psychiatric genetics offer suicidology? Crisis 2001; 22: 61–65.

    Article  CAS  PubMed  Google Scholar 

  2. Isometsa E, Henriksson M, Marttunen M, Heikkinen M, Aro H, Kuoppasalmi K et al. Mental disorders in young and middle aged men who commit suicide 1. BMJ 1995; 310: 1366–1367.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Maris RW . Suicide. Lancet 2002; 360: 319–326.

    Article  PubMed  Google Scholar 

  4. Mann JJ . Neurobiology of suicidal behaviour. Nat Rev Neurosci 2003; 4: 819–828.

    Article  CAS  PubMed  Google Scholar 

  5. Henriksson MM, Aro HM, Marttunen MJ, Heikkinen ME, Isometsa ET, Kuoppasalmi KI et al. Mental disorders and comorbidity in suicide. Am J Psychiatry 1993; 150: 935–940.

    Article  CAS  PubMed  Google Scholar 

  6. Mann JJ . The neurobiology of suicide. Nat Med 1998; 4: 25–30.

    Article  CAS  PubMed  Google Scholar 

  7. Asberg M, Traskman L, Thoren P . 5-HIAA in the cerebrospinal fluid. A biochemical suicide predictor? Arch Gen Psychiatry 1976; 33: 1193–1197.

    Article  CAS  PubMed  Google Scholar 

  8. Arango V, Underwood MD, Mann JJ . Postmortem findings in suicide victims. Implications for in vivo imaging studies. Ann NY Acad Sci 1997; 836: 269–287.

    Article  CAS  PubMed  Google Scholar 

  9. Mann JJ, Waternaux C, Haas GL, Malone KM . Toward a clinical model of suicidal behavior in psychiatric patients. Am J Psychiatry 1999; 156: 181–189.

    CAS  PubMed  Google Scholar 

  10. Purselle DC, Nemeroff CB . Serotonin transporter: a potential substrate in the biology of suicide. Neuropsychopharmacology 2003; 28: 613–619.

    Article  CAS  PubMed  Google Scholar 

  11. Joiner Jr TE, Brown JS, Wingate LR . The psychology and neurobiology of suicidal behavior. Annu Rev Psychol 2005; 56: 287–314.

    Article  PubMed  Google Scholar 

  12. Niswender CM, Herrick-Davis K, Dilley GE, Meltzer HY, Overholser JC, Stockmeier CA et al. RNA editing of the human serotonin 5-HT2C receptor. alterations in suicide and implications for serotonergic pharmacotherapy. Neuropsychopharmacology 2001; 24: 478–491.

    Article  CAS  PubMed  Google Scholar 

  13. Gurevich I, Tamir H, Arango V, Dwork AJ, Mann JJ, Schmauss C . Altered editing of serotonin 2C receptor pre-mRNA in the prefrontal cortex of depressed suicide victims. Neuron 2002; 34: 349–356.

    Article  CAS  PubMed  Google Scholar 

  14. Iwamoto K, Kato T . RNA editing of serotonin 2C receptor in human postmortem brains of major mental disorders. Neurosci Lett 2003; 346: 169–172.

    Article  CAS  PubMed  Google Scholar 

  15. Gott JM, Emeson RB . Functions and mechanisms of RNA editing. Annu Rev Genet 2000; 34: 499–531.

    Article  CAS  PubMed  Google Scholar 

  16. Bass BL . RNA editing by adenosine deaminases that act on RNA. Annu Rev Biochem 2002; 71: 817–846.

    Article  CAS  PubMed  Google Scholar 

  17. Valente L, Nishikura K . ADAR gene family and A-to-I RNA editing: diverse roles in posttranscriptional gene regulation. Prog Nucleic Acid Res Mol Biol 2005; 79: 299–338.

    Article  CAS  PubMed  Google Scholar 

  18. Burns CM, Chu H, Rueter SM, Hutchinson LK, Canton H, Sanders-Bush E et al. Regulation of serotonin-2C receptor G-protein coupling by RNA editing. Nature 1997; 387: 303–308.

    Article  CAS  PubMed  Google Scholar 

  19. Higuchi M, Single FN, Kohler M, Sommer B, Sprengel R, Seeburg PH . RNA editing of AMPA receptor subunit GluR-B: a base-paired intron-exon structure determines position and efficiency. Cell 1993; 75: 1361–1370.

    Article  CAS  PubMed  Google Scholar 

  20. Hoopengardner B, Bhalla T, Staber C, Reenan R . Nervous system targets of RNA editing identified by comparative genomics. Science 2003; 301: 832–836.

    Article  CAS  PubMed  Google Scholar 

  21. Hanrahan CJ, Palladino MJ, Bonneau LJ, Reenan RA . RNA editing of a Drosophila sodium channel gene. Ann NY Acad Sci 1999; 868: 51–66.:51–66.

    Article  CAS  PubMed  Google Scholar 

  22. Schmauss C . Regulation of serotonin 2C receptor pre-mRNA editing by serotonin. Int Rev Neurobiol 2005; 63: 83–100.

    Article  CAS  PubMed  Google Scholar 

  23. Chen CX, Cho DS, Wang Q, Lai F, Carter KC, Nishikura K . A third member of the RNA-specific adenosine deaminase gene family, ADAR3, contains both single- and double-stranded RNA binding domains. RNA 2000; 6: 755–767.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Niswender CM, Copeland SC, Herrick-Davis K, Emeson RB, Sanders-Bush E . RNA editing of the human serotonin 5-hydroxytryptamine 2C receptor silences constitutive activity. J Biol Chem 1999; 274: 9472–9478.

    Article  CAS  PubMed  Google Scholar 

  25. Wang Q, O'Brien PJ, Chen CX, Cho DS, Murray JM, Nishikura K . Altered G protein-coupling functions of RNA editing isoform and splicing variant serotonin2C receptors. J Neurochem 2000; 74: 1290–1300.

    Article  CAS  PubMed  Google Scholar 

  26. Fitzgerald LW, Iyer G, Conklin DS, Krause CM, Marshall A, Patterson JP et al. Messenger RNA editing of the human serotonin 5-HT2C receptor. Neuropsychopharmacology 1999; 21: 82S–90S.

    Article  CAS  PubMed  Google Scholar 

  27. Herrick-Davis K, Grinde E, Niswender CM . Serotonin 5-HT2C receptor RNA editing alters receptor basal activity: implications for serotonergic signal transduction. J Neurochem 1999; 73: 1711–1717.

    Article  CAS  PubMed  Google Scholar 

  28. Berg KA, Cropper JD, Niswender CM, Sanders-Bush E, Emeson RB, Clarke WP . RNA-editing of the 5-HT(2C) receptor alters agonist-receptor-effector coupling specificity. Br J Pharmacol 2001; 134: 386–392.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Price RD, Weiner DM, Chang MS, Sanders-Bush E . RNA editing of the human serotonin 5-HT2C receptor alters receptor-mediated activation of G13 protein. J Biol Chem 2001; 276: 44663–44668.

    Article  CAS  PubMed  Google Scholar 

  30. McGrew L, Price RD, Hackler E, Chang MS, Sanders-Bush E . RNA editing of the human serotonin 5-HT2C receptor disrupts transactivation of the small G-protein RhoA. Mol Pharmacol 2004; 65: 252–256.

    Article  CAS  PubMed  Google Scholar 

  31. Dracheva S, Davis KL, Chin B, Woo DA, Schmeidler J, Haroutunian V . Myelin-associated mRNA and protein expression deficits in the anterior cingulate cortex and hippocampus in schizophrenia. Neurobiol Dis 2006; 79: 157–173.

    Google Scholar 

  32. Dracheva S, Elhakem SL, Marcus SM, Siever LJ, McGurk SR, Haroutunian V . RNA editing and alternative splicing of human serotonin 2C receptor in schizophrenia. J Neurochem 2003; 87: 1402–1412.

    Article  CAS  PubMed  Google Scholar 

  33. Canton H, Emeson RB, Barker EL, Backstrom JR, Lu JT, Chang MS et al. Identification, molecular cloning, and distribution of a short variant of the 5-hydroxytryptamine2C receptor produced by alternative splicing. Mol Pharmacol 1996; 50: 799–807.

    CAS  PubMed  Google Scholar 

  34. Dracheva S, McGurk SR, Haroutunian V . mRNA expression of AMPA receptors and AMPA receptor binding proteins in the cerebral cortex of elderly schizophrenics. J Neurosci Res 2005; 79: 868–878.

    Article  CAS  PubMed  Google Scholar 

  35. Livak KJ, Schmittgen TD . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001; 25: 402–408.

    Article  CAS  PubMed  Google Scholar 

  36. Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol 2002; 3 (RESEARCH0034): 1–12.

    Article  Google Scholar 

  37. Hedeker D, Gibbons RD . MIXREG: a computer program for mixed-effects regression analysis with autocorrelated errors. Comput Methods Programs Biomed 1996; 49: 229–252.

    Article  CAS  PubMed  Google Scholar 

  38. Siever LJ, Buchsbaum MS, New AS, Spiegel-Cohen J, Wei T, Hazlett EA et al. d,l-fenfluramine response in impulsive personality disorder assessed with fluorodeoxyglucose positron emission tomography. Neuropsychopharmacology 1999; 20: 413–423.

    Article  CAS  PubMed  Google Scholar 

  39. Turecki G . Dissecting the suicide phenotype: the role of impulsive-aggressive behaviours. J Psychiatry Neurosci 2005; 30: 398–408.

    PubMed  PubMed Central  Google Scholar 

  40. Coccaro EF, Siever LJ, Klar HM, Maurer G, Cochrane K, Cooper TB et al. Serotonergic studies in patients with affective and personality disorders. Correlates with suicidal and impulsive aggressive behavior. Arch Gen Psychiatry 1989; 46: 587–599.

    Article  CAS  PubMed  Google Scholar 

  41. Vitali P, Basyuk E, Le Meur E, Bertrand E, Muscatelli F, Cavaille J et al. ADAR2-mediated editing of RNA substrates in the nucleolus is inhibited by C/D small nucleolar RNAs. J Cell Biol 2005; 169: 745–753.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Gurevich I, Englander MT, Adlersberg M, Siegal NB, Schmauss C . Modulation of serotonin 2C receptor editing by sustained changes in serotonergic neurotransmission. J Neurosci 2002; 22: 10529–10532.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Li D, He L . Meta-analysis supports association between serotonin transporter (5-HTT) and suicidal behavior. Mol Psychiatry 2007; 12: 47–54.

    Article  PubMed  Google Scholar 

  44. Arango V, Huang YY, Underwood MD, Mann JJ . Genetics of the serotonergic system in suicidal behavior. J Psychiatr Res 2003; 37: 375–386.

    Article  PubMed  Google Scholar 

  45. Anguelova M, Benkelfat C, Turecki G . A systematic review of association studies investigating genes coding for serotonin receptors and the serotonin transporter: II. Suicidal behavior. Mol Psychiatry 2003; 8: 646–653.

    Article  CAS  PubMed  Google Scholar 

  46. Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996; 274: 1527–1531.

    Article  CAS  PubMed  Google Scholar 

  47. Briley M, Moret C . Neurobiological mechanisms involved in antidepressant therapies. Clin Neuropharmacol 1993; 16: 387–400.

    Article  CAS  PubMed  Google Scholar 

  48. Pandey GN, Dwivedi Y, Ren X, Rizavi HS, Faludi G, Sarosi A et al. Regional distribution and relative abundance of serotonin(2c) receptors in human brain: effect of suicide. Neurochem Res 2006; 31: 167–176.

    Article  CAS  PubMed  Google Scholar 

  49. Serrats J, Mengod G, Cortes R . Expression of serotonin 5-HT2C receptors in GABAergic cells of the anterior raphe nuclei. J Chem Neuroanat 2005; 29: 83–91.

    Article  CAS  PubMed  Google Scholar 

  50. Eberle-Wang K, Mikeladze Z, Uryu K, Chesselet MF . Pattern of expression of the serotonin2C receptor messenger RNA in the basal ganglia of adult rats. J Comp Neurol 1997; 384: 233–247.

    Article  CAS  PubMed  Google Scholar 

  51. Di Matteo V, Cacchio M, Di Giulio C, Esposito E . Role of serotonin(2C) receptors in the control of brain dopaminergic function. Pharmacol Biochem Behav 2002; 71: 727–734.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Postmortem brain tissue was donated by The Stanley Medical Research Institute's array collection courtesy of Drs Michael B Knable, E Fuller Torrey, Maree J Webster and Robert H Yolken. This study was supported by VA Merit award to SD and by the VISN3 Mental Illness Research and Education Clinical Center (MIRECC) (LJS, VH and SD). We thank Dr William M Byne for his help in the preparation of the article.

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Correspondence to S Dracheva.

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Dracheva, S., Patel, N., Woo, D. et al. Increased serotonin 2C receptor mRNA editing: a possible risk factor for suicide. Mol Psychiatry 13, 1001–1010 (2008). https://doi.org/10.1038/sj.mp.4002081

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