17β-Estradiol regulates histone alterations associated with memory consolidation and increases Bdnf promoter acetylation in middle-aged female mice

Histone acetylation is essential for hippocampal memory formation in young adult rodents. Although dysfunctional histone acetylation has been associated with age-related memory decline in male rodents, little is known about whether histone acetylation is altered by aging in female rodents. In young female mice, the ability of 17β-estradiol (E(2)) to enhance object recognition memory consolidation requires histone H3 acetylation in the dorsal hippocampus. However, the extent to which histone acetylation is regulated by E(2) in middle-aged females is unknown. The mnemonic benefits of E(2) in aging females appear to be greatest in middle age, and so pinpointing the molecular mechanisms through which E(2) enhances memory at this age could lead to the development of safer and more effective treatments for maintaining memory function without the side effects of current therapies. Here, we show that dorsal hippocampal infusion of E(2) rapidly enhanced object recognition and spatial memory, and increased histone H3 acetylation in the dorsal hippocampus, while also significantly reducing levels of histone deacetylase (HDAC2 and HDAC3) proteins. E(2) specifically increased histone H3 acetylation at Bdnf promoters pII and pIV in the dorsal hippocampus of both young and middle-aged mice, despite age-related decreases in pI and pIV acetylation. Furthermore, levels of mature BDNF and pro-BDNF proteins in the dorsal hippocampus were increased by E(2) in middle-aged females. Together, these data suggest that the middle-aged female dorsal hippocampus remains epigenetically responsive to E(2), and that E(2) may enhance memory in middle-aged females via epigenetic regulation of Bdnf.