Estrogen receptor alpha and beta specific agonists regulate expression of synaptic proteins in rat hippocampus

Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Brain research (Impact Factor: 2.84). 08/2009; 1290:1-11. DOI: 10.1016/j.brainres.2009.06.090
Source: PubMed


Changes in hippocampal CA1 dendritic spine density and synaptic number across the estrous cycle in female rats correlate with increased hippocampal-dependent cognitive performance in a manner that is dependent on estrogen receptors (ERs). Two isoforms of the estrogen receptor, alpha and beta are present in the rat hippocampus and distinct effects on cognitive behavior have been described for each receptor. The present study generated a profile of synaptic proteins altered by administration of estradiol benzoate, the ERalpha selective agonist PPT (1,3,5-tris (4-hydroxyphenyl)-4-propyl-1H-pyrazole) and the ERbeta selective agonist DPN (2,3-bis (4-hydroxyphenyl) propionitrile) alone and in combination in comparison to vehicle in the CA1 region of the dorsal hippocampus. In the stratum radiatum, estradiol, DPN, and PPT increased PSD-95 and AMPA-type glutamate receptor subunit GluR1. Only DPN administration regulated expression of AMPA receptor subunits GluR2 and GluR3, increasing and decreasing levels respectively. DPN also increased GluR2 expression in the other lamina of the CA1. These results support previous reports that estradiol and isoform specific agonists differentially activate ERalpha and ERbeta to regulate protein expression. The distinct effects of DPN and PPT administration on synaptic proteins suggest that the desired therapeutic outcome of estrogen may be accomplished by using specific estrogen receptor agonists. Moreover, the effects of estradiol treatment on PSD-95 expression are consistent with a growing body of evidence that this postsynaptic protein is a key marker of estrogen action related to spine synapse formation.

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Available from: Bruce S Mcewen, Mar 12, 2014
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    • "For example, hippocampal PSD-95 synthesis can be induced by estradiol administration [16] [17]. It is inhibited by knockout of ER [18] but activated by estrogen nuclear receptor agonists [19] [20]. Our work also found that expression of hippocampal PSD-95 could be regulated by ovary estrogens in a time-dependent manner [21]. "
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    ABSTRACT: Hippocampus local estrogen which is converted from androgen that catalyzed by aromatase has been shown to play important roles in the regulation of learning and memory as well as cognition through action on synaptic plasticity, but the underlying mechanisms are poorly understood. Steroid receptor coactivator-1 (SRC-1) is one of the coactivator of steroid nuclear receptors; it is widely distributed in the brain areas that related to learning and memory, reproductive regulation, sensory and motor information integration. Previous studies have revealed high levels of SRC-1 immunoreactivities in the hippocampus; it is closely related to the levels of synaptic proteins such as PSD-95 under normal development or gonadectomy, but its exact roles in the regulation of these proteins remains unclear. In this study, we used aromatase inhibitor letrozole in vivo and SRC-1 RNA interference in vitro to investigate whether SRC-1 mediated endogenous estrogen regulation of hippocampal PSD-95. The results revealed that letrozole injection synchronously decreased hippocampal SRC-1 and PSD-95 in a dose-dependant manner. Furthermore, when SRC-1 specific shRNA pool was applied to block the expression of SRC-1 in the primary hippocampal neuron culture, both immunocytochemistry and Western blot revealed that levels of PSD-95 were also decreased significantly. Taking together, these results provided the first evidence that SRC-1 mediated endogenous estrogen regulation of hippocampal synaptic plasticity by targeting expression of synaptic protein PSD-95. Additionally, since letrozole is frequently used to treat estrogen-sensitive breast cancer, the above results also indicate its potential side effects in clinical administration. Copyright © 2015. Published by Elsevier Ltd.
    The Journal of steroid biochemistry and molecular biology 07/2015; 154. DOI:10.1016/j.jsbmb.2015.07.011 · 3.63 Impact Factor
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    • "Previous studies in the hippocampus have suggested that ER b may play a key role in mediating E2 effects upon synaptic plasticity, rapid release of glutamate and hippocampal -dependent cognitive function [46] [24]. However, other studies using ER selective agonists have implicated both ERa and ER b in mediating E2 plasticity effects in the hippocampus [44] [47]. Since ER b is expressed at a much higher level than ERa in the cerebral cortex, it is possible it may mediate E2 plasticity effects in the cortex. "
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    ABSTRACT: The steroid hormone, 17β-estradiol (E2) has been reported to enhance executive functions that are known to be mediated by the prefrontal cortex (PFC), although the underlying mechanisms remain unclear. To shed light on the potential mechanisms, we examined the effect of E2 in vivo upon spine density in the rat PFC and the somatosensory cortex (SSC), which has been implicated to be a transient storage site for information that can also contribute to working memory. The results revealed that E2 significantly enhanced the number of dendritic spines in both the SSC and PFC, as well as the expression of spinophilin. In vitro studies revealed further mechanistic insights by demonstrating that E2 enhanced AMPA GluR1 receptor expression and excitatory glutamatergic synapse formation in rat cortical neurons, without an effect upon inhibitory GABAergic synapse formation. Furthermore, E2 rapidly enhanced ERK and Akt activation in cortical neurons, and inhibitors of ERK and Akt activation significantly attenuated E2 induction of excitatory glutamatergic synapses. Administration of E2-BSA likewise significantly enhanced excitatory glutamatergic synapses in cortical neurons, and administration of an ER antagonist, ICI182,780 and a non-NMDA receptor antagonist (NBQX) significantly attenuated the effect of E2 upon enhancement of excitatory glutamatergic synapses, suggesting mediation by extranuclear estrogen receptors and involvement of non-NMDA receptor activation and signaling. As a whole, the studies demonstrate that E2 enhances spine density in both the PFC and SSC, and that E2 enhances excitatory glutamatergic synapse formation in cortical neurons via a rapid extranuclear ER-mediated signaling mechanism that involves up-regulation of GluR1 and mediation by Akt and ERK signaling pathways.
    Steroids 06/2013; 78(6):614-623. DOI:10.1016/j.steroids.2012.12.005 · 2.64 Impact Factor
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    • "The potent estrogen 17b-estradiol (E 2 ) is a critical regulator of hippocampal synaptic morphology. In rodents and nonhuman primates , E 2 increases hippocampal levels of synaptic proteins, including the presynaptic proteins synaptophysin and syntaxin, and the postsynaptic proteins spinophilin and PSD-95 (Brake et al. 2001; Frick et al. 2002; Choi et al. 2003; Spencer et al. 2008; Waters et al. 2009). E 2 also significantly increases hippocampal CA1 dendritic spine density in rodents and nonhuman primates (Woolley and McEwen 1992, 1993; Hao et al. 2003; Frick et al. 2004). "
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    ABSTRACT: The mammalian target of rapamycin (mTOR) signaling pathway is an important regulator of protein synthesis and is essential for various forms of hippocampal memory. Here, we asked whether the enhancement of object recognition memory consolidation produced by dorsal hippocampal infusion of 17β-estradiol (E(2)) is dependent on mTOR signaling in the dorsal hippocampus, and whether E(2)-induced mTOR signaling is dependent on dorsal hippocampal phosphatidylinositol 3-kinase (PI3K) and extracellular signal-regulated kinase (ERK) activation. We first demonstrated that the enhancement of object recognition induced by E(2) was blocked by dorsal hippocampal inhibition of ERK, PI3K, or mTOR activation. We then showed that an increase in dorsal hippocampal ERK phosphorylation 5 min after intracerebroventricular (ICV) E(2) infusion was also blocked by dorsal hippocampal infusion of the three cell signaling inhibitors. Next, we found that ICV infusion of E(2) increased phosphorylation of the downstream mTOR targets S6K (Thr-421) and 4E-BP1 in the dorsal hippocampus 5 min after infusion, and that this phosphorylation was blocked by dorsal hippocampal infusion of inhibitors of ERK, PI3K, and mTOR. Collectively, these data demonstrate for the first time that activation of the dorsal hippocampal mTOR signaling pathway is necessary for E(2) to enhance object recognition memory consolidation and that E(2)-induced mTOR activation is dependent on upstream activation of ERK and PI3K signaling.
    Learning & memory (Cold Spring Harbor, N.Y.) 02/2013; 20(3):147-55. DOI:10.1101/lm.026732.112 · 3.66 Impact Factor
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