Duration of estrogen deprivation, not chronological age, prevents estrogen's ability to enhance hippocampal synaptic physiology

Abstract

Whether estrogen replacement is beneficial to cognitive health is controversial. Some studies have shown that estrogen replacement therapy (ERT) relieves memory impairment associated with menopause in women, whereas others suggest that estrogen not only is incapable of providing a benefit, but actually can be detrimental. One possible explanation for this discrepancy in study findings could be the varying time after menopause at which ERT is initiated. It has been proposed that a critical period exists during which ERT must be administered to enhance cognitive function. This idea has yet to be tested directly using functional synaptic studies, however. Here we investigated whether prolonged hormone deprivation caused by ovariectomy (OVX) in young adult rats prevents the ability of estrogen replacement to increase synaptic function in the hippocampus to a degree necessary for estrogen-induced improvement in learning and memory. Remarkably, estrogen replacement was found to increase long-term potentiation, the current mediated by NR2B-containing NMDA receptors, and the dendritic spine density at CA3-CA1 synapses up to 15 months post-OVX. However, by 19 months post-OVX, the same estrogen replacement was unable to induce these changes. Importantly, this loss of estrogen's effectiveness was seen to be a consequence of the duration of deprivation. In female rats aged with their ovaries intact and examined at the same chronological age as the 19-month post-OVX group, estrogen replacement significantly increased synaptic function and spine density. These data clearly demonstrate that a critical period exists during which ERT must be administered, and that once this period passes, the beneficial effects are lost.C ognitive function fluctuates across the menstrual cycle in women, with increased learning occurring when plasma estrogen levels are highest (1, 2). As such, loss of endogenous estrogen production after menopause, a consequence of normal aging, has been correlated with cognitive deficits (3). Treatment with estrogen replacement therapy (ERT) is not always successful in alleviating this hormone-related cognitive decline (4, 5). This lack of benefit of ERT may be explained by the critical period hypothesis, which proposes that there is a critical period after reproductive senescence during which estrogen is capable of increasing hippocampal function to a sufficient degree to enhance memory processing. After this period, ERT might be ineffective and possibly even detrimental (6, 7).Hippocampal learning is increased during proestrus in cycling rats, and this effect can be mimicked in young adult ovariectomized (OVX) rats treated with the ovarian estrogen 17β-estradiol (E2) (8-11). Similar to women, rats that experience long-term ovarian hormone deprivation no longer benefit from E2's effects on enhancing hippocampal learning (12-15). The role of ovarian hormone senescence in the effectiveness of E2 replacement in enhancing learning is difficult to distinguish from normal aging processes, given that aging alone is kn...

Sex steroid hormones matter for learning and memory: estrogenic regulation of hippocampal function in male and female rodents

“…As such, fundamental changes may occur in the brain during chronic treatment (e.g., downregulation of ERs) that do not occur after acute treatment. On the other end of the hormonal spectrum, long-term ovariectomy decreased hippocampal neurogenesis and prevented acute E 2 from increasing cell proliferation (Tanapat et al 2005), which is consistent with the detrimental effects of long-term ovariectomy on LTP and memory discussed above Smith et al 2010;Vedder et al 2014). Collectively, these data suggest that either chronically elevated E 2 levels or long-term hormone deprivation may permanently alter the hippocampus to reduce its responsiveness to E 2 .…”

“…In these studies, two injections of E 2 given 24 h apart were unable to increase LTP in rats ovariectomized for 19 mo prior to treatment (Smith et al 2010). Importantly, this loss was not due to aging, as rats of the same age ovariectomized just 1 mo prior to E 2 treatment exhibited increased LTP in response to E 2 (Smith et al 2010).…”

“…In these studies, two injections of E 2 given 24 h apart were unable to increase LTP in rats ovariectomized for 19 mo prior to treatment (Smith et al 2010). Importantly, this loss was not due to aging, as rats of the same age ovariectomized just 1 mo prior to E 2 treatment exhibited increased LTP in response to E 2 (Smith et al 2010). This research group also found that treatment with both acute and chronic E 2 was unable to enhance object recognition memory in rats ovariectomized for 19 mo prior to treatment (Vedder et al 2014), suggesting important parallels between the synaptic and mnemonic responsiveness to E 2 in females.…”

C terminus of Hsc70-interacting protein (CHIP)-mediated degradation of hippocampal estrogen receptor-α and the critical period hypothesis of estrogen neuroprotection

“…S3). It should be pointed out that degradation of ERα following LTED may explain not only the loss of E2 neuroprotective action observed in our study but the loss of other critical E2 actions reported previously following LTED, such as loss of E2 enhancement of long-term potentiation (LTP) and synaptic density (24) and elevation of choline acetyltransferase (25). Thus, our results may help to explain the loss of other well-known estrogen actions in the hippocampus following prolonged hypoestrogenicity.…”

Cognition, mood, and physiological concentrations of sex hormones in the early and late postmenopause

“…These generally nonsignificant findings in younger and older postmenopausal women contrast with results of studies in rodents and nonhuman primates. Here, E2 affects cognitive performance, synaptic plasticity, and neurophysiological properties in a manner that can vary with age or the interval between ovariectomy and hormone replacement (10,(32)(33)(34)(35). Effects are tissue-specific and may reflect, in part, the increased degradation of estrogen receptor-α that occurs with aging or after ovariectomy (36,37).…”