5-HT_2CR is a member of the seven transmembrane-spanning G-protein coupled receptors. It is widely distributed in the nucleus accumbens (ACC), amygdala (AMY), hippocampus, and hypothalamus. This receptor is involved in the regulation of anxiety, mood, and food intake. 5-HT_2CR is subjected to RNA editing at five sites by adenosine deaminases acting on RNA. As a result of 5-HT_2CR RNA-editing, 24 different editing isoforms are potentially expressed in specific brain regions. In vitro studies showed that 5-HT_2CR RNA-editing leads to decrease in 5-HT potency, agonist binding affinity, constitutive activities, and G protein coupling activity, suggesting that RNA-editing may modulate serotonergic systems in the brain. Thus 5HT_2CR RNA-editing may have causative relevance to neuropsychiatric disorders.
Previously, mice expressing either the completely-edited isoform (VGV-mice) or non-edited isoform (INI-mice) were generated and phenotypic analyses of them have been performed. VGV-mice exhibited reduced fat mass despite hyperphagia and enhanced anxiety-like behavior, whereas INI-mice showed impairment of enhanced alcohol preference after chronic alcohol exposure.
To elucidate more detailed phenotypes of INI-mice, we performed the measurement of monoamines in various brain areas, elevated plus maze test (EPM), forced swimming test (FST), and tail suspension test. The levels of 5-HT were significantly decreased in the ACC, AMY, and striatum of INI-mice although dopamine and norepinephrine (NE) were unchanged. In the FST, INI-mice exhibited a significant increase in depression-like behavior. Moreover, we examined the sensitivity of INI-mice to the tricyclic antidepressant desipramine, a 5-HT and NE reuptake inhibitor. The reduced immobility time in FST after administration of desipramine at moderate dose was observed only in INI-mice, suggesting that INI-mice are more sensitive to desipramine. Taken together, our results demonstrate that 5-HT_2CR fine-tuning by RNA-editing plays important roles in higher brain functions.