Astrocytic estrogen receptors and impaired neurotrophic responses in a rat model of perimenopause

Todd E. Morgan, Caleb E. Finch

In a perimenopausal model of middle-aged rats, the astrocyte estrogen receptor-alpha (ERa): ER-beta (ERb) ratio increased with the onset of acyclicity (constant estrus, CE) in association with impaired neurotrophic responses to estradiol (E2). We report additional data on irregular cycling (IR) from this study of 9 month old perimenopausal subgroups. In particular, irregular cyclers (IR) also show increased ERa:ERb ratio in cerebral cortex astrocytes comparable to acyclic individuals in CE. In mixed glial cultures from these same cycling subgroups, the E2-dependent neurotrophic activity and glial fibrillary acidic protein (GFAP) repression by E2 were impaired in IR to the same degree as in CE-derived glia. The greater importance of cycling status than age during the perimenopause to astrocyte ERs are attributable to individual variations of the residual ovarian follicle pool, which determine the onset of acyclicity. The corresponding loss of E2-dependent GFAP repression and E2-dependent neurotrophic activity add further to the inverse relationship of GFAP expression and astrocyte neurotrophic activity across aging in both sexes. These findings are relevant to impairments of spatial learning and of hippocampal long-term potentiation during the onset of IR in middle-aged rats, and to perimenopausal factors mediating the higher risk of women for Alzheimer disease.