Authors: Linda A. Bean, Ashok Kumar, Asha Rani, Mike Guidi, Awilda M. Rosario, Pedro E. Cruz, Todd E. Golde, and Thomas C. Foster
Summary: 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 α (ERα) or estrogen receptor β (ERβ) 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 ERα, ERβ, or green fluorescent protein (GFP) in the CA1 region of the dorsal hippocampus. Animals were subsequently treated for 5 weeks with cyclic injections of 17β-estradiol-3-benzoate (EB, 10 μg) or oil vehicle. Spatial memory was examined 48 h after EB/oil treatment. EB treatment in the GFP (GFP + EB) and ERβ (ERβ + EB) groups failed to improve episodic spatial memory relative to oil-treated animals, indicating closing of the critical window. Expression of ERβ failed to improve cognition and was associated with a modest learning impairment. Cognitive benefits were specific to animals expressing ERα that received EB treatment (ERα + EB), such that memory was improved relative to ERα + oil and GFP + EB. Similarly, ERα + EB animals exhibited enhanced NMDAR-mediated synaptic transmission compared with the ERα + 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 ERα.
Source:
The Journal of Neuroscience; 35(49), 16077-16093 (12/09/15)