The Molecular Components of Estrogen Receptor Beta (ERβ) Signaling in Neuronal Sytems

With increasing life expectancy, women are now living upwards of 50 years without circulating estrogens, therefore, it is essential to investigate how the brain is changed by estrogen deprivation and also how aging influences these changes. The Women\u27s Health Initiative (WHI) study spurred rigorous debate regarding estrogen therapy for postmenopausal women due to dichotomous effects of estrogens in menopausal and post-menopausal women. Meta-analyses of the WHI study revealed that after circulating estrogens are depleted for many years re-exposure may cause aberrant, negative health effects, indicating that there is an age-related `switch\u27 in estrogen signaling around menopause. These age-related effects of HT expose a gap in scientific knowledge as to how estrogen receptors, ERα and ERβ signal when the body is deprived of estrogen and under the natural context of aging. ERβ regulates a number of genes governing grievous symptoms menopausal symptoms such as anxiety, depression, and cognitive decline. Further, alternative splice variants derived from ERβ do not bind estrogens as well as ERβ1, and importantly, ERβ splice variants increase in the brain with age. I hypothesized that altered splice variant signaling contributes to a switch in estrogen signaling around the time of menopause. Herein, I demonstrate that human ERβ splice variants are constitutively active transcription factors, supporting my hypothesis. I also describe another contribution to ERβ functions in the brain resulting from age and E2-dependent changes in protein:protein interactions with ERβ. This dissertation reveals 1) the varied transcriptional effects of ERβ alternative splice variants, 2) identification of novel ERβ protein interaction partners, 3) how these interactions and the expression of these proteins change as a factor of age and 4) the effects of changes in these interactions on gene transcription which could be part of the switch in molecular signaling of estrogens at the time of menopause