Estradiol-Induced Increase in the Magnitude of Long-Term Potentiation Is Prevented by Blocking NR2B-Containing Receptors

Smith, Caroline C.; McMahon, Lori L.

doi:10.1523/jneurosci.5279-05.2006

Cited by 170 publications

(185 citation statements)

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“…Our findings clearly support the critical period hypothesis, because E2 replacement in female rats up to 15 months, but not 19 months, post-OVX remains able to increase synaptic function and spine density, mimicking the effects of E2 in young adult OVX rats after a 2-wk deprivation (23,26). The preserved beneficial effects of E2 replacement in 21-mo-old rats (of the same chronological age as the 19-mo post-OVX group) measured at 1 mo post-OVX strongly indicates that the period of E2 deprivation, rather than chronological age, is the limiting factor in determining whether E2 replacement remains beneficial for hippocampal function.…”

Section: Discussionsupporting

confidence: 82%

“…2 D and E). These results mimic our previous findings in young adult OVX rats treated with this same E2 regimen at 2 wk post-OVX (23,26).…”

Section: E2-induced Increase In Ltp Magnitude Is Lost After Prolongedsupporting

confidence: 90%

“…1C). The ability of the same E2 replacement regimen to increase the LTP magnitude at 9 and 15 We previously reported that in young adult OVX rats, the increase in LTP magnitude occurs only when transmission mediated by NR2B-containing NMDARs, the NMDAR/AMPAR ratio, and spine density are increased simultaneously (23,26). Thus, the effects of prolonged E2 deprivation on the LTP magnitude in E2-treated animals predicts that NR2B transmission, NMDAR/AMPAR ratio, and spine density will be increased at 15 mo, but not at 19 mo, post-OVX.…”

Section: E2-induced Increase In Ltp Magnitude Is Lost After Prolongedmentioning

confidence: 99%

“…Estrogenic conditions that enhance learning in rats, including proestrus and treatment of OVX rats with exogenous E2, enhance LTP and dendritic spine density in CA3-CA1 synapses (19)(20)(21)(22)(23)(24). E2 also enhances the phosphorylation of NR2 NMDAR subunits (25) and selectively increases NMDAR current mediated by NR2B-containing receptors, which increases the NMDAR/AMPAR ratio and causes an increase in LTP magnitude (26,27). Previous studies of hippocampal function have correlated changes such as these to increased learning, likely because they underlie enhanced synaptic plasticity (28, 29).…”

mentioning

confidence: 99%

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

Smith

Vedder

Nelson

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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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...

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Section: Discussionsupporting

confidence: 82%

“…2 D and E). These results mimic our previous findings in young adult OVX rats treated with this same E2 regimen at 2 wk post-OVX (23,26).…”

Section: E2-induced Increase In Ltp Magnitude Is Lost After Prolongedsupporting

confidence: 90%

Section: E2-induced Increase In Ltp Magnitude Is Lost After Prolongedmentioning

confidence: 99%

mentioning

confidence: 99%

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

Smith

Vedder

Nelson

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…The enhancement of GluN2B NMDA receptor transmission by estradiol signaling might involve synaptic recruitment of GluN2B-containing NMDA receptors (Snyder et al, 2011). Estradiol-mediated enhancement of GluN2B function and synaptic plasticity have been reported in other brain areas (Smith and McMahon, 2006;Snyder et al, 2011;Xiao et al, 2013). Given the role of brain-derived neurotrophic factor (BDNF) downstream of estradiol signaling and its effect on GluN2B-mediated transmission, BDNF might be involved in estradiol-induced augmentation of GluN2B transmission (Levine and Kolb, 2000;Miranda et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

Regulation of the Mouse Medial Prefrontal Cortical Synapses by Endogenous Estradiol

Galvin

Ninan

2014

Neuropsychopharmacol

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Recent studies suggest that low endogenous estradiol might be a susceptibility factor for anxiety and trauma-related disorders in women. Consistently, fear extinction, a form of inhibitory learning critical for the management of anxiety symptoms, is positively correlated with endogenous estradiol levels. To understand the synaptic basis of the effect of endogenous estradiol on fear extinction, we studied glutamatergic transmission and plasticity in the infralimbic medial prefrontal cortex (IL-mPFC), a brain region crucial for the regulation of fear extinction. Diestrus mice (low estradiol) exhibited a higher basal glutamatergic transmission compared with proestrus mice (high estradiol). Synaptic plasticity was also regulated by endogenous estradiol, which favored synaptic potentiation in a GluN2B-dependent manner. Activation of estrogen receptor b (ERb) but not ERa rescued synaptic potentiation in diestrus mice by enhancing GluN2B-mediated NMDA receptor transmission. Our results suggest that both endogenous estradiol and ERb activation facilitate the ability of the IL-mPFC synapses to undergo potentiation, a mechanism necessary for the regulation of fear extinction.

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Increased coupling of caveolin‐1 and estrogen receptor α contributes to the fragile X syndrome

Yang

Zhang

et al. 2015

Annals of Neurology

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Estradiol-Induced Increase in the Magnitude of Long-Term Potentiation Is Prevented by Blocking NR2B-Containing Receptors

Cited by 170 publications

References 48 publications

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

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

Regulation of the Mouse Medial Prefrontal Cortical Synapses by Endogenous Estradiol

Increased coupling of caveolin‐1 and estrogen receptor α contributes to the fragile X syndrome

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