Early Life Stress Alters Adult Serotonin 2C Receptor Pre-mRNA Editing and Expression of the α Subunit of the Heterotrimeric G-Protein Gq

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Abstract
Infant maternal separation, a paradigm of early life stress in rodents, elicits long-lasting changes in gene expression that persist into adulthood. In BALB/c mice, an inbred strain with spontaneously elevated anxiety and stress reactivity, infant maternal separation led to increased depression-like behavioral responses to adult stress and robustly increased editing of serotonin 2C receptor pre-mRNA. Chronic fluoxetine treatment of adult BALB/c mice exposed to early life stress affected neither their behavioral responses to stress nor their basal 5-HT2Cpre-mRNA editing phenotype. However, when fluoxetine was administered during adolescence, depression-like behavioral responses to stress were significantly diminished in these mice, and their basal and stress-induced 5-HT2Cpre-mRNA editing phenotypes were significantly lower. Moreover, when BALB/c mice exposed to early life stress were raised in an enriched postweaning environment, their depression-like behavioral responses to adult stress were also significantly diminished. However, their 5-HT2Cpre-mRNA editing phenotype remained unaltered. Hence, the similar behavioral effects of enrichment and fluoxetine treatment during adolescence were not accompanied by similar changes in 5-HT2Cpre-mRNA editing. Enriched and nonenriched BALB/c mice exposed to early life stress also exhibited significantly increased expression of mRNA and protein encoding the Gαq subunit of G-protein that couples to 5-HT2A/2Creceptors. In contrast, Gαq expression levels were significantly lower in fluoxetine-treated mice. These findings suggest that compensatory changes in Gαq expression occur in mice with persistently altered 5-HT2Cpre-mRNA editing and provide an explanation for the dissociation between 5-HT2Creceptor editing phenotypes and behavioral stress responses.