Re-Opening the Critical Window for Estrogen Therapy

A decline in estradiol (E2)-mediated cognitive benefits denotes a critical window for the therapeutic effects of E2, but the mechanism for closing of the critical window is unknown. We hypothesized that upregulating the expression of estrogen receptor alpha (ER alpha) or estrogen receptor beta (ER beta) in the hippocampus of aged animals would restore the therapeutic potential of E2 treatments and rejuvenate E2-induced hippocampal plasticity. Female rats (15 months) were ovariectomized, and, 14 weeks later, adeno-associated viral vectors were used to express ER alpha, ER beta, or green fluorescent protein (GFP) in the CA1 region of the dorsal hippocampus. Animals were subsequently treated for 5 weeks with cyclic injections of 17 beta-estradiol-3-benzoate (EB, 10 mu g) or oil vehicle. Spatial memory was examined 48 h after EB/oil treatment. EB treatment in the GFP (GFP + EB) and ER beta (ER beta + EB) groups failed to improve episodic spatial memory relative to oil-treated animals, indicating closing of the critical window. Expression of ER beta failed to improve cognition and was associated with a modest learning impairment. Cognitive benefits were specific to animals expressing ER alpha that received EB treatment (ER alpha + EB), such that memory was improved relative to ER alpha + oil and GFP + EB. Similarly, ER alpha + EB animals exhibited enhanced NMDAR-mediated synaptic transmission compared with the ER alpha + oil and GFP + EB groups. This is the first demonstration that the window for E2-mediated benefits on cognition and hippocampal E2 responsiveness can be reinstated by increased expression of ER alpha.