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

Abstract

Suicide is a major public health problem with B1 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-HT 2C R) 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-HT 2C R 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-HT 2C R, that is, VSV (Val156-Ser158-Val160). Because the VSV isoform of 5-HT 2C R 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.

Serotonin receptor 2C and mental disorders: Genetic, expression, and RNA editing studies

“…[32][33][34]39,47 Consistent with them, we also confirmed that reduced expression level of HTR2C did not affect editing level in brains of patients. Therefore, expression level of HTR2C is not likely to affect RNA editing level in brains of patients with mental disorders.…”

“…33 Recently, Dracheva et al examined RNA editing status in SZ and BD using different cohorts. 32 Although they again did not find editing alterations in patients with SZ, they detected significant decrease of VGV isoform in BD. Moreover, they provide further evidence of association of altered RNA editing and suicide.…”

Ionotropic glutamate receptor mRNA editing in the prefrontal cortex: no alterations in schizophrenia or bipolar disorder

“…24,27 Later studies demonstrated an association between 5-HT 2C R editing and suicide. [23][24][25][26] In particular, one study conducted in our laboratory, which used samples from the same cohort and brain region as the present study, showed that the specimens from individuals who had committed suicide displayed greater 5-HT 2C R editing than those from individuals who died from other causes, regardless of psychiatric diagnosis. 26 One could hypothesize that if these differences in editing were the result of greater ADAR activity in suicide completers, the editing efficiency of other ADAR substrates would also be elevated in these individuals.…”

“…21,22 In addition, editing of another neurotransmitter receptor, the serotonin 2C receptor (5-HT 2C R), has been implicated in schizophrenia, depression and suicide. [23][24][25][26][27][28] However, editing in iGluRs has never been comprehensively assessed in the human brain in the context of psychiatric conditions within the same brain region.…”

Newly identified ADAR-mediated A-to-I editing positions as a tool for ALS research

“…16,17,19,29,30 The editing of A-to-I positions in the 5-HT 2c receptor was observed to increase in the victims of suicide among patients with depression or schizophrenia, thus suggesting that 5-HT 2c receptor mRNA editing may be associated with changes in mood but not with comorbid psychiatric illnesses. 31 Indeed, the extent of RNA editing at these sites differs among mouse strains and was altered after the administration of antidepressants or exposure to a stressful environment in normal mouse brains. 16,32,33 An A-to-I conversion of glutamate receptor subunits markedly alters the channel properties of glutamate receptors and hence, the neuronal excitability as a whole.…”