Altered Isoform Expression of the Serotonin 2C Receptor Disrupts Normal Maternal Care

Abstract

RNA transcripts encoding the 2C-subtype of the serotonin (5HT2C) receptor are modified by adenosine-to-inosine editing events to generate as many as twenty-four 5HT2C receptor protein isoforms. These modified receptors are expressed in a region-specific manner in the central nervous system (CNS) and demonstrate differences in their constitutive activity and efficacy to interact with specific G-proteins. To determine the physiologic relevance of 5HT2C RNA editing, I generated mutant mice solely expressing the non-edited isoform (5HT2C-INI) of the receptor. Heterozygous mutant dams display profound behavioral deficits in maternal care including poor nest formation and altered pup retrieval that affect growth and anxiety-related behavior in both wild-type and mutant offspring. Treatment with a selective 5HT2C inverse agonist rescues deficits in pup retrieval, indicating that altered 5HT2C signaling underlies the observed alterations in maternal behavior. These studies not only indicate a role for 5HT2C signaling in maternal care, but also demonstrate the importance of normal patterns of 5HT2C RNA editing in vivo.