Serotonin 2C Receptor mRNA editing as a Molecular Correlate of Suicide

Suicide---the tenth leading cause of death in the U.S.---is a complex phenomenon with numerous biological and psychological risk factors. The presence of a psychiatric diagnosis---commonly major depression disorder (MDD), bipolar disorder (BPD), schizophrenia (SZ), or drug abuse---is the most consistent risk factor for suicide in the general population (Cavanagh et al., 2003; Nock et al., 2008). Genetic studies indicate that suicidal behavior is characterized by its own distinct pathophysiology, which is different from and/or independent of associated comorbid psychiatric conditions (Brent and Mann, 2005; Voracek and Loibl, 2007). One of the biological mechanisms that is associated with suicide is related to variations in RNA editing of the serotonin 2C receptor (5-HT2CR) in the brain (Dracheva et al., 2008; Gurevich et al., 2002b; Iwamoto and Kato, 2003; Niswender et al., 2001). Specifically, our lab has previously shown that suicide victims with an antemortem diagnosis of SZ or BPD have a higher level of 5-HT2CR mRNA editing (and by inference, a lower level of the receptor function) in the dorsolateral prefrontal cortex (DLPFC) compared to individuals of the same diagnosis that died of other causes (Dracheva et al., 2008). The molecular mechanisms of these observed editing alterations, however, remain elusive.;In an attempt to identify these mechanisms, I developed and evaluated a novel multiplex TaqMan qPCR editing assay and used it to investigate whether the observed suicide-associated alterations in 5-HT2CR editing may result from increased activity of the enzymes that catalyze mRNA editing, adenosine deaminases that act on RNA (ADARs). I found that the suicide-associated editing alteration is apparently unique to the 5-HT2CR, as editing of other ADAR substrates, ionotropic glutamate receptor subunits (iGluRs) and ADAR2, remained unchanged in the DLPFC of BPD and SZ suicides. In addition, through the course of this study, I made an important observation with respect to the editing patterns of specific iGluR alternative splicoforms in the human brain. The interplay between editing and splicing which I detected in these iGluR subunits may play a significant role in moderating the sensitivity of the resulting receptor to glutamate.;Basal extracellular serotonin has been proposed as a potential trigger for the modulation of 5-HT2CR editing efficiency. Because of the importance of serotonergic system in suicide, I investigated this hypothesis by comparing 5-HT2CR editing among rodent and human models of altered extracellular serotonin [serotonin transporter (SERT) knock-out rats and humans with different functional SERT and monoamine oxidase A polymorphisms]. My findings argue against the notion that extracellular serotonin availability triggers 5-HT2CR editing alterations. Instead, editing may serve as a homeostatic mechanism that adjusts 5-HT2CR function in order to compensate for a possible detrimental effect of genetic polymorphisms within genes whose products comprise the 5-HT2CR functional network. To begin testing this hypothesis, I compared 5-HT2CR editing patterns among individuals with different 5-HT2CR SNPs genotypes. Although only trend level associations between editing and these 5-HT2CR genotypes were observed, other SNPs within the gene may prove to be significantly associated with higher 5-HT2CR editing.;Since thirty percent of all suicides occur in the context of an MDD diagnosis (Cornelius et al., 1995; Oquendo et al., 2004) and there is evidence linking MDD to dysfunction of the serotonin system (Frisch et al., 1999; Maes and Meltzer, 1995; Owens and Nemeroff, 1994; Stockmeier et al., 1998), I assessed the 5-HT2CR editing in the DLPFC of a cohort of MDD subjects and detected suicide-associated changes similar to those previously noted in BPD and SZ suicides. This finding confirmed that increased 5-HT2CR editing in the DLPFC is a suicide-specific phenomenon, consistent throughout the three most common comorbid disorders.