Effect of enriched environment on serotonin and RNA editing of serotonin 2C receptor is specific for brain regions and mouse strains

Abstract

Serotonin neurotransmission is sensitive to environmental stimuli. Serotonin receptor 2C (HTR2C) undergoes dynamic A-to-I editing that fine-tunes cell response to serotonin and is altered in depressed suicide victims and by pharmacological treatments. We aimed to explore a mediating role of Htr2c mRNA editing in response to enriched environment and factors involved in this response. Three-week-old BALB/c and C57BL/6 male mice were housed in enriched and standard conditions for four weeks. Htr2c mRNA editing pattern and expression, serotonin level and expression of Adar and Adarb1 mRNAs (coding enzymes catalyzing A-to-I editing) and Snord115 RNA (regulating Htr2c mRNA alternative splicing and editing) were measured in prefrontal cortex (PFC) and hippocampus (HC), brain regions implicated in suicidal behavior. BALB/c mice, a “stress-sensitive” strain due to genetically determined lower serotonin level, responded to enriched conditions by adapting the Htr2c editing pattern to a slight serotonin decrease in PFC and a significant increase in HC. C57BL/6 mice, a “stress-resilient” strain, responded to enriched environment by increasing the serotonin level and changing Adar and Adarb1 mRNAs expression in HC, and without changes in PFC. Our findings suggest that the enriched environment effect on the serotonin level and a mediating role of Htr2c mRNA editing in PFC depend on the genetic background and its interactions with the environment. On the other hand, changes in HC are primarily driven by enriched environment. Our results imply usefulness of enriched environment paradigm for understanding interactions of genetic and environmental factors underlying suicidal behavior, which might improve psychological treatments.