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In aging women, cognitive decline and increased risk of dementia have been associated with the cessation of ovarian hormones production at menopause. In the brain, presence of the key enzyme aromatase required for the synthesis of 17-β-estradiol (E2) allows for local production of E2 in absence of functional ovaries. Understanding how aromatase activity is regulated could help alleviate the cognitive symptoms. In female rodents, genetic or pharmacological reduction of aromatase activity over extended periods of time impair memory formation, decreases spine density, and hinders long-term potentiation (LTP) in the hippocampus. Conversely, increased excitatory neurotransmission resulting in rapid N-methyl-d-aspartic acid (NMDA) receptor activation rapidly promotes neuroestrogen synthesis. This rapid modulation of aromatase activity led us to address the hypothesis that acute neuroestrogens synthesis is necessary for LTP at the Schaffer collateral-cornu ammonis 1 (CA1) synapse in absence of circulating ovarian estrogens. To test this hypothesis, we did electrophysiological recordings of field excitatory postsynaptic potential (fEPSPs) in hippocampal slices obtained from ovariectomized mice. To assess the impact of neuroestrogens synthesis on LTP, we applied the specific aromatase inhibitor, letrozole, before the induction of LTP with a theta burst stimulation protocol. We found that blocking aromatase activity prevented LTP. Interestingly, exogenous E2 application, while blocking aromatase activity, was not sufficient to recover LTP in our model. Our results indicate the critical importance of rapid, activity-dependent local neuroestrogens synthesis, independent of circulating hormones for hippocampal synaptic plasticity in female rodents., (© 2024 The Author(s). Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.)

Females experience depression, posttraumatic stress disorder (PTSD), and anxiety disorders at approximately twice the rate of males, but the mechanisms underlying this difference remain undefined. The effect of sex hormones on neural substrates presents a possible mechanism. We investigated the effect of ovariectomy at two ages, before puberty and in adulthood, and 17β-estradiol (E2) replacement administered chronically in drinking water on anxiety level, fear memory formation, and extinction. Based on previous studies, we hypothesized that estradiol replacement would impair fear memory formation and enhance extinction rate. Females, age 4 weeks and 10 weeks, were divided randomly into 4 groups; sham surgery, OVX, OVX+low E2 (200nM), and OVX+high E2 (1000nM). Chronic treatment with high levels of E2 significantly increased anxiety levels measured in the elevated plus maze. In both age groups, high levels of E2 significantly increased contextual fear memory but had no effect on cued fear memory. In addition, high E2 decreased the rate of extinction in both ages. Finally, catechol-O-methyltransferase (COMT) is important for regulation of catecholamine levels, which play a role in fear memory formation and extinction. COMT expression in the hippocampus was significantly reduced by high E2 replacement, implying increased catecholamine levels in the hippocampus of high E2 mice. These results suggest that estradiol enhanced fear memory formation, and inhibited fear memory extinction, possibly stabilizing the fear memory in female mice. This study has implications for a neurobiological mechanism for PTSD and anxiety disorders., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Downstream regulatory element antagonist modulator (DREAM)/calsenilin(C)/K⁺ channel interacting protein 3 (KChIP3) is a multifunctional Ca²⁺-binding protein highly expressed in the hippocampus that inhibits hippocampus-sensitive memory and synaptic plasticity in male mice. Initial studies in our lab suggested opposing effects of DR/C/K3 expression in female mice. Fluctuating hormones that occur during the estrous cycle may affect these results. In this study, we hypothesized that DR/C/K3 interacts with 17β-estradiol, the primary estrogen produced by the ovaries, to play a role in hippocampus function. We investigated the role of estradiol and DR/C/K3 in learning strategy in ovariectomized (OVX) female mice. OVX WT and DR/C/K3 knockout (KO) mice were given three injections of vehicle (sesame oil) or 17β-estradiol benzoate (0.25 mg in 100 mL sesame oil) 48, 24, and 2 h before training and testing. DR/C/K3 and estradiol had a time-dependent effect on strategy use in the female mice. Male KO mice exhibited enhanced place strategy relative to WT 24 h after pre-exposure. Fear memory formation was significantly reduced in intact female KO mice relative to intact WT mice, and OVX reduced fear memory formation in the WT, but had no effect in the KO mice. Long-term potentiation in hippocampus slices from female mice was enhanced by circulating ovarian hormones in both WT and DR/C/K3 KO mice. Paired-pulse depression was not affected by ovarian hormones but was reduced in DR/C/K3 KO mice. These results provide the first evidence that DR/C/K3 plays a timing-dependent role in estradiol regulation of learning, memory, and plasticity.

Short-term oestradiol treatment modulates hippocampus-dependent memory and synaptic plasticity in the hippocampus. Long-term oestradiol treatment can also enhance hippocampus- dependent memory, although the effects of long-term oestradiol treatment on synaptic plasticity are unknown. We investigated the effects of long-term oestradiol treatment on synaptic plasticity at the Schaeffer Collateral/CA1 synapse in 8-month-old female rats. In addition, we determined the role of endogenous activation of muscarinic acetylcholine receptors (mAChRs) in synaptic transmission and plasticity using scopolamine (1 μm), an antagonist of mAChRs. Hippocampus slices from ovariectomised rats that were treated with oestradiol-containing capsules for 5 months were compared with slices from ovariectomised rats that received cholesterol-containing capsules. Unexpectedly, scopolamine application significantly increased the baseline field excitatory postsynaptic potentials (fEPSP) and decreased paired pulse facilitation (PPF) in slices from cholesterol-treated rats. Baseline fEPSPs and PPF were not significantly modulated in slices from oestradiol-treated rats by scopolamine. Slices from oestradiol-treated rats showed enhanced long-term potentiation relative to slices from cholesterol-treated rats. Scopolamine significantly reduced the magnitude of plasticity in slices from oestradiol-treated rats. Taken together, these results suggest that mAChRs have a significant effect on baseline synaptic transmission through a decrease in the probability of glutamate release in slices from cholesterol-treated rats. Long-term oestradiol treatment blocks this effect and enhances theta-burst stimulation-induced synaptic plasticity in the middle-aged female rat, and this effect is mediated by activation of mAChRs., (© 2012 The Authors. Journal of Neuroendocrinology © 2012 Blackwell Publishing Ltd.)