Functional relevance of serotonin 2C receptor mRNA editing in antidepressant- and anxiety-like behaviors

Serotonin 2C receptors (5-HT(2C)R) have been shown to undergo post-transcriptional RNA editing. This modification affects the affinity, coupling and constitutive activity of the receptor. In vivo, manipulations such as stress or antidepressant administration dramatically modify the pattern of 5-HT(2C)R mRNA editing, suggesting that this phenomenon might be involved in the pathophysiology of stress-related disorders. Indeed, alterations of 5-HT(2C)R mRNA editing have been observed in depressed patients. Thus, the recent development of mice expressing either the non-edited (5-HT(2C)R-INI) or the fully-edited form of 5-HT(2C)R (5-HT(2C)R-VGV) provides a novel opportunity to investigate the relevance of this phenomenon in the context of stress-related disorders. We observed that both 5-HT(2C)R-INI and 5-HT(2C)R-VGV mice exhibit exaggerated anxiety-like behaviors in the elevated-plus maze paradigm. This phenotype was observed when the INI or VGV mutations were present in mice on a BALB/c background, as well as non-significant trends in the same direction in mice on a C57BL/6J background. In animal models of antidepressant-like activity, the absence of editing of 5-HT(2C)R mRNA (5-HT(2C)R-INI) induced an increase in the time spent immobile in the forced-swim test (FST) and tail suspension test (TST). Complete editing of 5-HT(2C) receptor mRNA (5-HT(2C)R-VGV) induced antidepressant-like behavior in the FST and TST, as reflected by a significant decrease in time spent immobile. These phenotypes were unrelated to alterations in locomotor activity in both 5-HT(2C)R-INI and 5-HT(2C)R-VGV. In the TST, these phenotypes were accompanied by a decrease and an increase in response to desipramine in 5-HT(2C)R-INI and 5-HT(2C)R-VGV, respectively. These data constitute the first in vivo demonstration of a role for 5-HT(2C)R mRNA editing in anxiety- and depression-related behaviors.