Hippocampal epigenetic modification at the brain-derived neurotrophic factor gene induced by an enriched environment.

Environmental enrichment is an experimental paradigm that increases brain-derived neurotrophic factor (BDNF) gene expression accompanied by neurogenesis in the hippocampus of rodents. In the present study, we investigated whether an enriched environment could cause epigenetic modification at the BDNF gene in the hippocampus of mice. Exposure to an enriched environment for 3-4 weeks caused a dramatic increase in the mRNA expression of BDNF, but not platelet-derived growth factor A (PDGF-A), PDGF-B, vascular endothelial growth factor (VEGF), nerve growth factor (NGF), epidermal growth factor (EGF), or glial fibrillary acidic protein (GFAP), in the hippocampus of mice. Under these conditions, exposure to an enriched environment induced a significant increase in histone H3 lysine 4 (H3K4) trimethylation at the BDNF P3 and P6 promoters, in contrast to significant decreases in histone H3 lysine 9 (H3K9) trimethylation at the BDNF P4 promoter and histone H3 lysine 27 (H3K27) trimethylation at the BDNF P3 and P4 promoters without any changes in the expression of their associated histone methylases and demethylases in the hippocampus. The expression levels of several microRNAs in the hippocampus were not changed by an enriched environment. These results suggest that an enriched environment increases BDNF mRNA expression via sustained epigenetic modification in the mouse hippocampus.