Physiological roles of edited serotonin 2C receptor isoforms

Abstract

RNA transcripts encoding the 2C-subtype of serotonin receptor (5-HT2CR) undergo up to five A-to-I editing events to generate distinct 5-HT2CR isoforms that differ in their constitutive activity and the efficacy of receptor:G-protein interactions. To determine the physiologic relevance of 5-HT2CR editing, we have generated mutant mice solely expressing either the non-edited (INI) or fully-edited (VGV) isoforms of the receptor. Mutant mice expressing the non-edited receptor have decreased 5-HT2CR mRNA levels and a concomitant decrease in receptor binding, suggesting a compensatory homeostatic mechanism by which to maintain normal levels of serotonergic signaling. Mutant mice further demonstrate behaviors characteristic of altered maternal care including poor nest formation, pup scattering and diminished pup size. Both wild-type and mutant pups raised by mutant mice show anxiety-related behaviors and a decreased growth rate compared to offspring raised by wild-type dams, indicating that the genotype of the dams is responsible for phenotypic alterations. Mutant mice solely expressing the VGV receptor isoform demonstrate a 70% decrease in growth rate during the first three weeks of postnatal development, whereas the rates of growth for VGV and wild-type animals are identical beyond postnatal day 21. Despite their decreased size, VGV-expressing mice demonstrate a paradoxical increase in food consumption after weaning, consistent with reduced 5-HT2CR signaling, yet this hyperphagia does not result in the adult-onset obesity previously observed in 5-HT2CR-null animals. These studies demonstrate the physiologic importance of 5-HT2CR editing and provide animal models to further explore the role(s) that the 5-HT2CR plays in metabolism, as well as behavioral and neuropsychiatric disorders.