Elsevier

Neuroscience

Volume 141, Issue 4, 2006, Pages 1793-1800
Neuroscience

Cellular neuroscience
Both estrogen receptor α and estrogen receptor β agonists enhance cell proliferation in the dentate gyrus of adult female rats

https://doi.org/10.1016/j.neuroscience.2006.05.032Get rights and content

Abstract

This study investigated the involvement of estrogen receptors α and β in estradiol-induced enhancement of hippocampal neurogenesis in the adult female rat. Subtype selective estrogen receptor agonists, propyl-pyrazole triol (estrogen receptor α agonist) and diarylpropionitrile (estrogen receptor β agonist) were examined for each receptor’s contribution, individual and cooperative, for estradiol-enhanced hippocampal cell proliferation. Estradiol increases hippocampal cell proliferation within 4 h [Ormerod BK, Lee TT, Galea LA (2003) Estradiol initially enhances but subsequently suppresses (via adrenal steroids) granule cell proliferation in the dentate gyrus of adult female rats. J Neurobiol 55:247–260]. Therefore, animals received s.c. injections of estradiol (10 μg), propyl-pyrazole triol and diarylpropionitrile alone (1.25, 2.5, 5.0 mg/0.1 ml dimethylsulfoxide) or in combination (2.5 mg propyl-pyrazole triol+2.5 mg diarylpropionitrile/0.1 ml dimethylsulfoxide) and 4 h later received an i.p. injection of the cell synthesis marker, bromodeoxyuridine (200 mg/kg). Diarylpropionitrile enhanced cell proliferation at all three administered doses (1.25 mg, P<0.008; 2.5 mg, P<0.003; 5 mg, P<0.005), whereas propyl-pyrazole triol significantly increased cell proliferation (P<0.0002) only at the dose of 2.5 mg. Our results demonstrate both estrogen receptor α and estrogen receptor β are individually involved in estradiol-enhanced cell proliferation. Furthermore both estrogen receptor α and estrogen receptor β mRNA was found co-localized with Ki-67 expression in the hippocampus albeit at low levels, indicating a potential direct influence of each receptor subtype on progenitor cells and their progeny. Dual receptor activation resulted in reduced levels of cell proliferation, supporting previous studies suggesting that estrogen receptor α and estrogen receptor β may modulate each other’s activity. Our results also suggest that a component of estrogen receptor–regulated cell proliferation may take place through alternative ligand and/or cell-signaling mechanisms.

Section snippets

Experimental procedures

All experiments were conducted in accordance with the policies established by the University of British Columbia, the Canadian Council on Animal Care and National Institutes of Health Guide for the Care and Use of Laboratory Animals regarding the ethical treatment of animals used for research. All efforts were made to reduce the number and the suffering of animals.

Estradiol-induced enhanced cell proliferation is mediated by both ER-α and ER-β in the dentate gyrus of adult OVX female rats

As expected, estradiol increased cell proliferation at the 4 h time period, with EB-treated females having significantly more labeled cells relative to OIL-treated females (P≤0.002; Fig. 1; main effect: F(9,42)=6.42; P≤0.00001). There was no statistical difference between the two vehicles groups, OIL and DMSO (P>0.14). The ER-α agonist, PPT significantly increased cell proliferation, relative to vehicle only at a dose of 2.5 mg (P≤0.0002; Fig. 1). However, analysis demonstrated that the ER-β

Both ER-α and ER-β are involved in estradiol-induced upregulation of cell proliferation

Consistent with previous literature we found that exposure to a high dose of estradiol for 4 h increased the number of BrdU-labeled cells (assessed 24 h post-BrdU) in adult female rats (Nagy et al 2006, Ormerod et al 2003). The ER-β agonist, DPN, showed a significant increase in cell proliferation at all three administered doses (1.25, 2.5 and 5 mg), whereas the ER-α agonist, PPT, demonstrated a significant increase in cell proliferation at a dose of 2.5 mg, relative to vehicle-treated rats.

Conclusions

In conclusion, we have shown that both ERs, α and β, are involved in estradiol-induced enhancement of hippocampal neurogenesis in the female rat. We also found that 24 h after treatment, there was co-localization of Ki-67 expressing cells with both ER-α and ER-β mRNA in the dentate gyrus. Our previous studies have demonstrated that estradiol has the ability to increase proliferation in a time-dependent manner and future studies will determine whether this increase in neurons has a functional

Acknowledgments

We gratefully acknowledge the technical assistance of Cindy Barha, Ziba Rajaei and Jennifer Barker. We thank Heather Cameron for her help with the confocal pictures. This work was funded by CIHR operating grants to L.A.M.G. and V.V. V.V. is a CHIR and MSFHR New Investigator. L.A.M.G. is a MSFHR Senior Scholar.

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      Furthermore, ERα, ERβ, and GPERs can activate cell signaling cascades that affect neuroplasticity (Foster, 2012; Waters et al., 2011). It is important to emphasize that the concentration of ERs or ARs in the hippocampus varies by hippocampus subfields, estrous cycle, exposure to exogenous estrogens, age, and sex (Adams et al., 2002; Bohacek & Daniel, 2009; Cui et al., 2013; Duarte-Guterman, Lieblich, et al., 2019; González et al., 2007; Hamson et al., 2013; Han et al., 2013; Matsuda et al., 2008; Mazzucco et al., 2006; Mitra et al., 2003; Mitterling et al., 2010; Xiao & Jordan, 2002). Evidence from several rodent species shows that endogenous estrogens (including estradiol and estrone) can influence hippocampal neurogenesis (Galea & McEwen, 1999; Ormerod and Galea, 2001; Ormerod, Lee, & Galea, 2003; Tanapat et al., 1999; Tanapat, Hastings, & Gould, 2005; Tzeng et al., 2014; Rummel, Epp, & Galea, 2010; reviewed in Galea et al., 2008; Duarte-Guterman, Yagi, Chow, & Galea, 2015).

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