The data discussed above support the hypothesis that histone acetylation could produce active demethylation of the GR exon 17 promoter, yet several questions remain unanswered. How, for example, is histone acetylation targeted to the exon 17 promoter as a consequence of maternal behavior? We propose that maternal behavior stimulates 5-HT, which stimulates NGFIA, and that NGFIA then targets HATs and eventually demethylases to the GR exon 17 promoter. To dissect the different molecular components of this hypothesis, we took advantage of both hippocampal primary neuronal cell cultures as well as nonneuronal cell lines. The two systems have different strengths and could be used to test different components of the model. First, we tested the hypothesis that 5-HT acts through cAMP to produce hypomethylation. Hippocampal cell cultures treated with either 5-HT or 8-bromo-cAMP, a stable cAMP analog, show increased GR expression following 4 days of treatment. Treatment of hippocampal cells in culture with 5-HT also results in the hypomethylation of the 5' CpG dinucleotide of the NGFIA consensus sequence within the exon 17 promoter of the GR gene, with no effect
