Early life stress is a prominent risk factor for adult-onset depressive illness. In both humans and rodents, early life stress leads to changes in several physiological measures that persist into adulthood. In a genetically distinct inbred strain of mice with lower forebrain serotonin, spontaneously elevated anxiety, and increased stress reactivity (Balb/c), early life stress leads to several changes in neuronal gene expression in adulthood. These changes include increased expression of serotonin 2C (5-HT2C) receptor mRNA isoforms that result from RNA editing and encode receptors with reduced function. Such changes in 5-HT2C receptor editing have also been found in brains of depressed suicide victims. Studies on Balb/c mice showed that changes in 5-HT2C receptor editing are accompanied by altered expression of the alpha subunit of Gq protein that couples to this receptor. They further showed that treatment with the antidepressant drug fluoxetine during adolescence significantly decreased the abnormally increased 5-HT2C pre-mRNA editing that resulted from early life stress and also reversed corresponding alterations in G alpha q protein expression. Similar to the effect of adolescent fluoxetine in mice exposed to early life stress, postweaning environmental enrichment diminished the magnitude of hightened behavioral responses to adult stress. However, in contrast to fluoxetine, postweaning enrichment did not alter the abnormal 5-HT2C pre-mRNA editing phenotype. In this proposal, a cross-fostering paradigm between Balb/c and stress-resistant C57Bl/6 mice is used to test the impact of genetic factors, environmental factors, and adolescent antidepressant treatment on the modulation of 5-HT2C receptor editing phenotypes. It further tests potential mechanisms leading to increased 5-HT2C pre-mRNA editing in Balb/c mice exposed to early life stress. One hypothesis is that early life stress alters the expression of distinct isoforms of the editing enzymes ADAR1/2 via alternative splicing to yield mRNA encoding enzymes with higher catalytic activities. Another hypothesis, tested with studies on transfected cells, is that G alpha q protein is a critical mediator of the serotonin-dependent regulation of 5-HT2C pre-mRNA editing. Finally, molecular and anatomic studies will demonstrate that changes in 5-HT2C pre-mRNA editing that result from early life stress are also accompanied by changes in the expression of other genes that are either potential mediators of epigenetic changes in gene expression, transcriptional or post-transcriptional modulators of gene expression, or involved in synaptic functions, and that many of these changes in gene expression are functionally linked to depression and differentially modulated by genetic factors, environmental influences, and antidepressant treatment.
