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

Abstract

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.

Estrogen promotes learning-related plasticity by modifying the synaptic cytoskeleton

“…Experiments of this kind failed to detect any steroid effects on the slope of the curve describing fiber volley amplitude and stimulation current in slices from male rats (Kramár et al, 2009a). Similarly, there were no evident differences from controls in the relationship between fiber volley and EPSP size across different intensities of stimulation in slices from OVX rats and mice (Smith and McMahon, 2005; Yun et al, 2007). Repetitive stimulation, at sites throughout the nervous system, increases transmitter release probability via accumulation of residual calcium in axon terminals.…”

“…Estrogen has a second, acute physiological action that is logically and experimentally related to memory encoding: it markedly facilitates long-term potentiation in male rats (Foy et al, 1999; Kramár et al, 2009a), and OVX rats (Smith and McMahon, 2005 and 2006) and mice (Yun et al, 2007). This involves both a reduced threshold for inducing LTP and an elevated ceiling on the maximum degree of potentiation produced by conventional stimulation paradigms (Fig 1B).…”

Midlife predictors of Alzheimer's disease

“…Factors that appear non-modifiable may have their influence attenuated by intervention. If initiated early, it is possible that aging related hormonal changes may be tempered by hormone therapy; hypertension, hypercholesterolaemia, obesity, and diabetes (all of which have genetic contributions) may be modified by diet, exercise, or pharmaceutical intervention; and even the effect of APOE, the most established genetic risk factor for late onset AD, appears to be modified by several factors including nutritional factors like B12 [124], alcohol consumption [125], exercise [126], estrogen [127, 128], antihypertensive treatment [129], and education [130]. …”

Long-Term Potentiation at CA3–CA1 Hippocampal Synapses with Special Emphasis on Aging, Disease, and Stress

“…Results demonstrate that modulation of AMPA receptor could be a possible mechanism involved in impaired LTP observed in ApoE knockouts (Valastro et al, 2001). For further readings, see Trommer et al (2004, 2005), Yun et al (2007), Korwek et al (2009), Chen et al (2010b), and Dumanis et al (2011). …”