Research
Suicide is tragic and preventable.
Suicide is a major, preventable public health problem. Research shows that risk factors for suicide include (1) depression, schizophrenia and other mental disorders, with more than 90 percent of people who die by suicide having a DSM IV diagnosis of psychiatric disorder (2) stressful life events, in combination with other risk factors, such as depression (3) prior suicide attempt (4) family history of mental disorder or substance abuse (5) family history of suicide (6) family violence, including physical or sexual abuse, perhaps leading to an anxiety disorder such as post-traumatic stress disorder (7) access to firearms or drugs (8) exposure to the suicidal behavior of others. Gender appears to play a role in suicide. While men are four times more likely to kill themselves, women are 2-3 times more likely to attempt suicide (www.afsp.org). Research also shows that the risk for suicide is associated with changes in neurotransmitter systems, including the serotonergic (5-HT), glutamatergic and GABAergic systems.
RNA editing and psychiatric disorders.
RNA editing is a post-transcriptional process which is predicted to modify up to 2000 transcripts in addition to 16% of known microRNAs1. RNA editing of the 5-HT2C receptor (5-HT2CR) occurs after hydrolytic deamination of 1-5 adenosine (A) residues, by enzymes called the Adenosine Deaminases Acting on RNA enzymes (or 'ADARs'). Editing of the 5-HT2C pre-mRNA by ADARs alters the amino acid sequence of the protein (Illustrated in Fig 1).
Figure 2: The double-stranded RNA loop of the human 5-HT2C receptor transcript. ADAR enzymes have been shown to bind only to double-stranded RNA. The specific sites of activity of ADARs 1 and 2 are indicated.
5-HT2C RNA editing modulates behavior and is altered in depression. RNA editing of the 5-HT2C receptor produces structural changes that alter G-protein coupling and constitutive activity of the receptor in vitro. The fully-edited isoform of the 5-HT2RC (VGV) has >40-fold decrease in serotonergic potency2. Mutant mice solely expressing the fully edited (VGV) isoform of the receptor (5-HT2CRVGV) exhibited >20-fold increases in 5-HT2CR protein levels in multiple brain regions. These mice modeled some of the symptoms of Prader-Willi syndrome3. Furthermore, mouse models of learned helplessness4 and anxiety5 also have altered 5-HT2C RNA editing.
5-HT2C expression is altered in mood disorders. Evidence from human post-mortem studies indicate that 5-HT2C transcript abundance is altered in suicide6 and schizophrenia7 and that these changes are unlikely to be caused by psychotropic medication8. In addition, increased 5-HT2C RNA editing in patients with depression and/or suicide victims has been observed in several studies9-12.
Figure 3 (left): Increased 5-HT2C RNA editing in major depression is probably due to increased ADAR1 in these subjects.
Expression of RNA editing enzymes was measured in the dorsolateral prefrontal cortex of postmortem subjects diagnosed with schizophrenia, major depression (MDD), bipolar disorder, and a comparison group (total n=60). ADAR1 expression was found to be significantly increased in major depressive suicide victims compared with patients who did not commit suicide. These data indicate that ADAR1 could play a role in the pathophysiology of suicide in patients with major depression13.
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