Aging and Loss of Circulating 17β-Estradiol Alters the Alternative Splicing of ERβ in the Female Rat Brain

Loss of circulating 17 beta-estradiol (E2) that occurs during menopause can have detrimental effects on cognitive function. The efficacy of hormone replacement therapy declines as women become farther removed from the menopausal transition, yet the molecular mechanisms underlying this age-related switch in E2 efficacy are unknown. We hypothesized that aging and varying lengths of E2 deprivation alters the ratio of alternatively spliced estrogen receptor (ER)beta isoforms in the brain of female rats. Further, we tested whether changes in global transcriptional activity and splicing kinetics regulate the alternative splicing of ER beta. Our results revealed brain region-specific changes in ER beta alternative splicing in both aging and E2-deprivation paradigms and showed that ER beta could mediate E2-induced alternative splicing. Global transcriptional activity, as measured by phosphorylated RNA polymerase II, was also regulated by age and E2 in specific brain regions. Finally, we show that inhibition of topoisomerase I resulted in increased ER beta 2 splice variant expression.