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

Abstract

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.

Figure 1. Alterations in 5-HT_2CR mRNA editing in BALB/c background result in increased anxiety-like behavior in the elevated plus maze

Both 5-HT_2CR-INI (A–E) and 5-HT_2CR-VGV mice (F–J) exhibit increases in anxiety-like behaviors, affecting latency to enter in open arms (A, F), time spent in open arms (B, G), the number of entries into open arms(C, H), head-dips (D, I) and rearings (E, J). Values are means +/−SEM. * p<0.05, ** p<0.01, and *** p<0.001 for significant difference from wild-type animals. Full statistical analysis can be found in Table 1.

Figure 2. The anxiety-related phenotype of 5HT_2CR-INI and 5-HT_2CR-VGV mice is attenuated in C57BL/6J genetic background

Both 5-HT_2CR-INI (A–E) and 5-HT_2CR-VGV mice (F–J) exhibit increases in anxiety-like behaviors, with significant decreases in head dips in both transgenic lines (D, I) and significantly decreased rearings in VGV mice (J) as compared to wildtype animals. Latency to enter open arms (A, F), time spent in open arms (B, G), and entries into open arms (C, H) were not significantly changed in INI or VGV mice as compared to wildtype animals. Values are means +/−SEM. * p < 0.05, ** p < 0.001, and *** p < 0.001 for significant difference from wild-type animals. Full statistical analysis can be found in Table 1.

Figure 3. Impact of alterations of 5-HT_2CR mRNA editing on despair behavior and antidepressant response in FST, TST and locomotor activity

5-HT_2CR-INI mice exhibit a pro-depressant phenotype in the FST (A) but not in the TST (B). Conversely, 5-HT_2CR-VGV mice exhibit an antidepressant-like phenotype in both the FST (D) and TST (E). Both lines showed significant decreases in immobility in both tests in response to DMI (A, B, D, and E), and the effect of DMI was potentiated in 5-HT_2CR-VGV in the TST but not the FST. DMI significantly decreased locomotor activity in both lines (C and F). There was no significant difference in locomotor activity in either line after vehicle injection (C and F), although there was a trend toward a decrease in the VGV mice (p = 0.09)(F). Values are means +/−SEM. * p < 0.05 and *** p < 0.001 for significant difference from respective saline-treated animals. # p < 0.05 for significant difference from respective wild-type animals. Full statistical analysis can be found in Table 1.