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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    • "Nuclear AR and ERs (ERa and ERb) have been detected in the hippocampus of several species [14] [15] [16]. AR and ERs show unique properties that affect the structure of the hippocampus and its function, including synaptic plasticity, learning and memory, and cognition [17] [18] [19] [20] [21] [22]. Additionally , the novel membrane estrogen receptor GPR30 (also called GPER-1) has been shown to mediate rapid, non-classic, estrogenic regulation on the hippocampus [23] [24]. "
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    ABSTRACT: Androgens have been proposed to play important roles in the regulation of hippocampus function either directly, through the androgen receptor (AR), or indirectly, through estrogen receptors (ERs), after aromatization into estradiol. Steroid receptor coactivator-1 (SRC-1) is present in the hippocampus of several species, and its expression is regulated by development and aging, as well as by orchidectomy and aromatase inhibitor letrozole administration, while ovariectomy only transiently downregulated hippocampal SRC-1. However, whether the expression of hippocampal SRC-1 can be directly regulated by testosterone, the principal male sex hormone, remains unclear. In the present study, we investigated the expression of hippocampal SRC-1 after orchidectomy and testosterone treatment using immunohistochemistry and Western blot analysis. We found that while hippocampal SRC-1 was significantly downregulated by orchidectomy (ORX), its expression was rescued by treatment with testosterone in a dose-dependent manner. Furthermore, we noticed that the decreased expression of hippocampal AR, ERs and the synaptic proteins GluR-1 and PSD-95 induced by ORX was also rescued by testosterone treatment in a dose-dependent manner. However, we found that hippocampal membrane estrogen receptor GPR30 and dendritic spine marker spinophilin were not altered by ORX or testosterone treatment. Together, the above results provided the first direct evidence for the androgenic regulation on hippocampal SRC-1, indicating that SRC-1 may be a direct target of androgenic regulation on the hippocampus. Furthermore, because AR and ERs can be differentially regulated by testosterone and the transcriptional activity requires the involvement of local SRC-1, and considering the complicated regulatory pathway of each individual receptor, the converged hub regulator SRC-1 of these nuclear receptor networks is worthy of further investigation.
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    • "In a subsequent experiment, RS (intact Ov) rats were treated with either an ER-b agonist [beta 2, 3-bis(4- hydroxyphenyl) propionitrile; DPN; 1 mg/kg; s.c. (Waters et al. 2009)] or dimethylsulfoxide every 48 h for 10 injections. Forty-eight hours after the last treatment, vehicle-or DPN-treated rats were killed for tissue collection or exposed to global cerebral ischemia. "
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    ABSTRACT: Periodic treatments with estrogen receptor subtype-β (ER-β) agonist reduce post-ischemic hippocampal injury in ovariectomized rats. However, the underlying mechanism of how ER-β agonists protect the brain remains unknown. Global cerebral ischemia activates the innate immune response, and a key component of the innate immune response is the inflammasome. This study tests the hypothesis that ER-β regulates inflammasome activation in the hippocampus, thus reducing ischemic hippocampal damage in reproductively senescent female rats that received periodic ER-β agonist treatments. First, we determined the effect of hippocampal ER-β silencing on the expression of the inflammasome proteins caspase-1, apoptosis-associated speck-like protein containing a CARD (ASC) and interleukin (IL)-1β. Silencing of ER-β attenuated 17β-estradiol mediated decrease in caspase-1, ASC and IL-1β. Next, we tested the hypothesis that periodic ER-β agonist treatment reduces inflammasome activation and ischemic damage in reproductively senescent female rats. Periodic ER-β agonist treatments significantly decreased inflammasome activation and increased post-ischemic live neuronal counts by 32% (p<0.05) as compared to the vehicle-treated, reproductively senescent rats. Current findings demonstrated that ER-β activation regulates inflammasome activation and protects the brain from global ischemic damage in reproductively senescent female rats. Further investigation on the role of a periodic ER-β agonist regimen to reduce the innate immune response in the brain could help reduce the incidence and the impact of global cerebral ischemia in post-menopausal women. This article is protected by copyright. All rights reserved.
    Full-text · Article · Oct 2015 · Journal of Neurochemistry
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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.
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