Increased estrogen receptor β expression correlates with decreased spine formation in the rat hippocampus

Szymczak, Sylwia; Kalita, Katarzyna; Jaworski, Jacek; Mioduszewska, Basia; Savonenko, Alena; Markowska, Alicja L.; Merchenthaler, Istvån; Kaczmarek, Leszek

doi:10.1002/hipo.20172

Cited by 47 publications

(45 citation statements)

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“…The role of estrogen and its receptors in changes of dendritic spines is not clear. Srivastava et al have shown that WAY-200070, an ERβ agonist, increased spine density (38), whereas Szymczak et al (39) found that estrogen induces spine density but that overexpression of ERβ in hippocampal neurons from embryonic rat brains by means of gene transfection, opposed the induction by estrogen. The discrepancies between the different results from these studies may be due to different treatment methods, models, and duration of treatment.…”

Section: Discussionmentioning

confidence: 99%

Reduction of dendritic spines and elevation of GABAergic signaling in the brains of mice treated with an estrogen receptor β ligand

Tan

Dai

et al. 2012

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

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An estrogen receptor (ER) β ligand (LY3201) with a preference for ERβ over ERα was administered in s.c. pellets releasing 0.04 mg/d. The brains of these mice were examined 3 d after treatment had begun. Although estradiol-17β is known to increase spine density and glutaminergic signaling, as measured by Golgi staining, a clear reduction in spines was evident on the dendritic branches in LY3201-treated mice but no morphological alteration and no difference in the number of dendritic spines on dendritic stems were observed. In the LY3201-treatment group, there was higher expression of glutamic acid decarboxylase (GAD) in layer V of cortex and in the CA1 of hippocampus, more GAD + terminals surrounding the pyramidal neurons and less glutamate receptor (NMDAR) on the neurons in layer V. There were no alterations in expression of Iba1 or in Olig2 or CNPase. However, GFAP + astrocytes were increased in the LY3201-treatment group. There were also more projections characteristic of activated astrocytes and increased expression of glutamine synthetase (GS). No expression of ERβ was detectable in the nuclei of astrocytes. Clearly, LY3201 caused a shift in the balance between excitatory and inhibitory neurotransmission in favor of inhibition. This shift was due in part to increased synthesis of GABA and increased removal of glutamate from the synaptic cleft by astrocytes. The data reveal that treatment with a selective ERβ agonist results in changes opposite to those reported in estradiol-17β-treated mice and suggests that ERα and ERβ play opposing roles in the brain.neurotransmitter | glutamate toxicity | cerebral cortex | hippocampus O f the two estrogen receptors (ERs), ERα appears to be the major player in regulating the reproductive system, whereas both receptors ERα and ERβ are involved in regulation of mood and affective disorders (1, 2). Several studies show that ERα activation is anxiogenic (3-5), whereas ERβ activation is anxiolytic and controls expression of fear and anxiety-like behaviors (6-9). Not surprisingly, estradiol (E2), which binds equally well to ERα and ERβ, has unpredictable effects on abnormal psychiatric behaviors, depending on dose, treatment regimens, or animal models (10-13). In hippocampal cultures both exogenous (E2) treatment and locally synthesized E2 up-regulate ERα and down-regulate ERβ expression (14). Thus, E2 has unpredictable effects on the balance between anxiogenic and anxiolytic effects, in part because E2 has opposite effects on ERα and ERβ (15). Using subtype-selective ligands, we can begin to study the outcome of selective activation or inhibition of a particular receptor subtype involved in different behaviors.Spines and the synapses located on neurons are the sites at which neuronal communication occurs and are essential for complex behavioral phenomena and cognition. In the mature CNS, alterations in synapse structure and function continue to be a dynamic process that is of fundamental importance to learning and memory as well as other adaptive abilities of the brain. Studies...

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Section: Discussionmentioning

confidence: 99%

Reduction of dendritic spines and elevation of GABAergic signaling in the brains of mice treated with an estrogen receptor β ligand

Tan

Dai

et al. 2012

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

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“…ERb isoform has been involved in the modulation of spine dendritic content in the hippocampus as a low level of its expression correlates with the estradiolinduced spine increase in pyramidal neurons (Szymczak et al, 2006). In the same line, ERb knockout mice are unable to learn a spatial task (Rissman et al, 2002;Liu et al, 2008), while the administration of an agonist of these receptors, but not an ERa agonist, improves the performance of mice in hippocampus-dependent memory tasks (Liu et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Differential Expression of Estrogen Receptors in Two Hippocampal Regions During the Estrous Cycle of the Rat

Mendoza-Garcés

Mendoza-Rodríguez

Jiménez-Trejo

et al. 2011

The Anatomical Record

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In the hippocampus, estrogens increase dendritic arborization, longterm potentiation, neuroprotection, and participate in many functions related with learning, memory, and affective behaviors. The presence of both estrogen receptors alpha (ERa) and beta (ERb) isoforms has been described in the hippocampus where they play different physiological roles. The aim of this study was to investigate, by using both techniques immunohistochemistry and Western Blot, the expression pattern of ERa and ERb in the hippocampus of the rat along the estrous cycle. Western blot analysis was used to confirm the specificity of the antibodies used against ERa and ERb and its relative content in the hippocampus. Results from immunohistochemical studies indicate that ERb expression increased more than the ERa in CA1 and CA3 regions during all phases of the estrous cycle. ERb immunoreactivity was mainly located in the nucleus and predominantly expressed in CA1 during estrous and metestrus, and in CA3 during diestrus. ERa was more abundant during estrous in comparison to other phases of the cycle in CA1 region, while it was more abundant during metestrus in CA3. Interestingly, the immunolocalization of ERa subtype was both cytoplasmic and nuclear. The overall results indicate that there is a differential expression, cellular localization, and distribution of both ER subtypes in CA1 and CA3 regions, suggesting different roles for these two receptors in the hippocampus along the estrous cycle. Anat Rec, 294:1913Rec, 294: -1919Rec, 294: , 2011. V V C 2011 Wiley-Liss, Inc.

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“…11,55 reduction of cytokines levels, T cells, and macrophages; 49,50,53 and downregulation of both astroglial proliferation and activation of astrocytes.…”

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confidence: 99%

“…Many studies have reported a primary role for ERa as a regulator of the antiinflammatory properties of estradiol, including the antiinflammatory and neuroprotective activity of estradiol, 3,9,55 neuroprotection after ischemia, 12,44,50 inhibition of microglial activation, and inhibition of high MMP-9 levels. 54 In addition, a growing number of studies have reported antiinflammatory roles for ERb, such as neuroprotection after ischemia, 1,8,57 inhibition of microglial activity, 4 suppression of transcription, and decreased levels of IL-1b, IL-6, TNFa, and chemokine CCL2.…”

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confidence: 99%

Contribution of estrogen receptors alpha and beta in the brain response to traumatic brain injury

Asl

Khaksari²,

Khachki

et al. 2013

JNS

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Object Although there is evidence that estradiol has neuroprotective effects after traumatic brain injury (TBI) in female rats, it is unclear which estrogen receptor (ER) subtype, ERα or ERβ, mediates this effect. The authors therefore examined the roles of the different ERs in this effect. Here the authors used the ERα selective agonist propyl pyrazole triol (PPT) and the ERβ selective agonist diarylpropionitrile (DPN) alone and in combination in female rats to investigate this question. Methods Before the ovariectomized animals were injured using the Marmarou TBI technique, they were randomly divided into the following 9 groups: control, sham, TBI, vehicle, E1 (physiological dose of 17-β estradiol), E2 (pharmacological dose of 17-β estradiol), PPT, DPN, and PPT+DPN. Levels of blood-brain barrier (BBB) disruption (5 hours) and water content (24 hours) were evaluated after TBI. In groups receiving drugs or vehicle, treatment was administered as a single dose intraperitoneally 30 minutes after induction of TBI. Results Results showed that brain edema or brain water content after TBI was lower (p < 0.001) in the E2, PPT, DPN, and PPT+DPN groups than it was in the vehicle group. After trauma, the Evans blue dye content or BBB permeability was significantly higher in the TBI and vehicle groups (p < 0.001) than in the E2, PPT, DPN, and PPT+DPN groups. The inhibitory effects of PPT+DPN on brain water content, neurological scores, and Evans blue dye content were the highest for all groups. Although both PPT and DPN increased neurological scores after TBI, PPT appears to be more effective in increasing neurological scores. Conclusions Neuroprotective effects of estradiol on brain edema, BBB permeability, and neurological scores are mediated through both ERα and ERβ. This may suggest a therapeutic potential in the brain trauma for ER-specific agonists.

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Increased estrogen receptor β expression correlates with decreased spine formation in the rat hippocampus

Cited by 47 publications

References 70 publications

Reduction of dendritic spines and elevation of GABAergic signaling in the brains of mice treated with an estrogen receptor β ligand

Reduction of dendritic spines and elevation of GABAergic signaling in the brains of mice treated with an estrogen receptor β ligand

Differential Expression of Estrogen Receptors in Two Hippocampal Regions During the Estrous Cycle of the Rat

Contribution of estrogen receptors alpha and beta in the brain response to traumatic brain injury

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