Editing of the serotonin 2C receptor pre-mRNA: Effects of the Morris Water Maze

Abstract

The pre-mRNA encoding the serotonin 2C receptor, HTR2C (official mouse gene symbol, Htr2c), is subject to adenosine deamination that produces inosine at five sites within the coding region. Combinations of this site-specific A-to-I editing can produce 32 different mRNA sequences encoding 24 different protein isoforms with differing biochemical and pharmacological properties. Studies in humans have reported abnormalities in patterns of HTR2C editing in psychiatric disorders, and studies in rodents show altered patterns of editing in response to drug treatments and stressful situations. To further explore the biological significance of editing of the Htr2c mRNA and its regulation, we have examined patterns of Htr2c editing in C57BL/6J mice after exposure to the hidden platform version of the Morris Water Maze, a test of spatial learning that, in mice, is also associated with stress. In brains of both swimming controls and mice trained to find the platform, subtle time dependent changes in editing patterns are seen as soon as one hour after a probe trial and typically last less than 24 hours. Changes in whole brain with cerebellum removed differ from those seen in isolated hippocampus and cortex. Unexpectedly, in hippocampi from subsets of mice, abnormally low levels of editing were seen that were not correlated with behavior or with editing levels in cortex. These data implicate responses to spatial learning and stress, in addition to stochastic processes, in the generation of subtle changes in editing patterns of Htr2c.

Analyses of differentially expressed genes after exposure to acute stress, acute ethanol, or a combination of both in mice

“…Exposure to different types of stressors can also result in different patterns of gene expression changes, and the use of a single type of acute stress is a caveat in the interpretation of the present results (Hueston et al, 2011; Joëls & Baram, 2009). An additional caveat is that gene expression changes were measured at only a single time point following the stress exposure, because time has previously been shown to be an important variable in the determination of which genes are differentially expressed (Aujla et al, 2013; Du, Stasko, Costo, Davisson, & Gardiner, 2007; Lima et al, 2016; Smith et al, 2016). …”

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

“…48 In contrast, DOI [(±)-1-(-4-iodo-2,5-dimethoxyphenyl)-2-aminopropane] treated mice showed opposite RNA editing alteration at E site compared to pCPA treatment. 48 Importantly, in the behavioral model of depression-related disorders, forced swimming, 48 learned helplessness, 39 water maize 49 and maternal separation 50 has been reported to alter RNA editing status. Although direction of change was not consistent across studies, drug-treatments such as fluoxetine 39,48,50 or imipramine 39 altered RNA editing pattern, which associated with improvement of behavioral abnormalities.…”

A Conservative, Single-Amino Acid Substitution in the Second Cytoplasmic Domain of the Human Serotonin2CReceptor Alters Both Ligand-Dependent and -Independent Receptor Signaling

“…In contrast, editing efficiency is decreased in the brains of schizophrenic patients (Sodhi et al, 2001). Likewise, changes in RNA editing occur in various animal models of anxiety (Hackler et al, 2006;Du et al, 2007) and depression (Iwamoto et al, 2005). Moreover, drugs that alter serotonin signaling and other psychoactive drugs also alter RNA editing efficiency (Gurevich et al, 2002a,b;Yang et al, 2004).…”