Estradiol enhances long term potentiation in hippocampal slices from aged apoE4-TR mice

Hormone replacement therapy to treat or prevent Alzheimer Disease (AD) in postmenopausal women is controversial because it may pose other health risks such as cancer and thromboembolism. ApoE status is thought to influence the nootropic efficacy of hormone therapy, but findings are neither consistent nor well understood. We used a known in vitro memory model (long-term potentiation, LTP) in aged (24-27 month) female targeted replacement mice expressing human apoE3 or E4 to compare the effects of exogenous estradiol. Recording medial perforant path evoked field potentials in dentate gyrus of hippocampal slices, we found that both strains exhibited comparable basal synaptic transmission as assessed by input/output functions and paired pulse depression, and that these measures were not affected by estradiol. Vehicle-treated groups from both strains showed comparable LTP. Estradiol had no effect on LTP in apoE3-TR, but selectively increased LTP magnitude in apoE4-TR. The estradiol induced enhancement of LTP in aged female apoE4-TR is consistent with recent clinical observations that estrogen replacement decreases AD risk in some women with apoE4. Elucidating the mechanism of this selective enhancement may lead to more informed treatment decisions as well as to the development of safer alternatives to hormone therapy.