Brain-derived estrogen: a critical player in maintaining cognitive health of aged female rats, possibly involving GPR30

Brain-derived estrogen is an endogenous neuroprotective agent, whether and how might this protective function with aging, especially postmenopausal drops in circulating estrogen, remain unclear. We herein subjected 6, 14, and 18 Mon female rats to mimic natural aging, and found that estrogen synthesis is more active in the healthy aged brain, as evidenced by the highest levels of mRNA and protein expression of aromatase, the key enzyme of E2 biosynthesis, among the three groups. Aromatase knockout in forebrain neurons (FBN-Aro-/-) impaired hippocampal and cortical neurons, and cognitive function in 18 Mon rats, compared to wild-type controls. Furthermore, estrogen nuclear receptors (ERα/β) displayed opposite changes, with a significant ERα decrease and ERβ increase, while membrane receptor GPR30 expressed stably in hippocampus during aging. Intriguingly, GPR30, but not ERα and ERβ, was decreased by FBN-Aro-/-. The results indicate that GPR30 is more sensitive to brain local E2 synthesis. Our findings provide evidence of a critical role for brain-derived estrogen in maintaining healthy brain function in older individuals, possibly involving GPR30.