Xu Hou, PhD; Samuel O. Adeosun, PhD; Xueying Zhao, PhD; Rosanne Hill, PhD; Baoying Zheng, MS; Reveena Reddy, MD; Xiao Su, PhD; Jeffrey Meyer, MD, PhD; Thomas Mosley, PhD; Jun Ming Wang, PhD
Background: Estrogen therapy (ET), an effective treatment for perimenopausal depression, often fails to ameliorate symptoms when initiated late after the onset of menopause. Our previous work has suggested that alternative splicing of RNA might mediate these differential effects of ET.
Methods: Female Sprague–Dawley rats were treated with estradiol (E2) or vehicle 6 days (early ET) or 180 days (late ET) after ovariectomy (OVX). We investigated the differential expression of RNA splicing factors and tryptophan hydroxylase 2 (TPH2) protein using a customized RT2 Profiler PCR Array, reverse-transcription polymerase chain reaction, immunoprecipitation and behaviour changes in clinically relevant early and late ET.
Results: Early ET, but not late ET, prolonged swimming time in the forced swim test and reduced anxiety-like behaviours in the elevated plus maze. It reversed OVX-increased (SFRS7 and SFRS16) or OVX-decreased (ZRSR2 and CTNNB1) mRNA levels of splicing factors and ERβ splicing changes in the brains of OVX rats. Early ET, but not late ET, also increased the expression of TPH2 and decreased monoamine oxidase A levels in the dorsal raphe in the brains of OVX rats. In late ET, only diarylpropionitrile (an ERβ-specific agonist) achieved similar results — not E2 (an ERα and ERβ agonist) or propylpyrazoletriol (an ERα-specific agonist).
Limitations: Our experimental paradigm mimicked early and late ET in the clinical setting, but the contribution of age and OVX might be difficult to distinguish.
Conclusion: These findings suggest that ERβ alternative splicing and altered responses in the regulatory system for serotonin may mediate the antidepressant efficacy of ET associated with the timing of therapy initiation. It is likely that ERβ-specific ligands would be effective estrogen-based antidepressants late after the onset of menopause.
Submitted Oct. 10, 2017; Revised Feb. 22, 2018; Accepted Mar. 10, 2018; Published online Aug. 14, 2018
Acknowledgments: This study was supported by an Alzheimer’s Association Investigator Initiated Research Grant (133086), a Carraway foundation grant, a training grant from a center grant from the National Center for Research Resources (P30 GM103328, PI: CS), a component of the National Institutes of Health, and a MIND center subcontract to J.M. Wang. The authors greatly appreciate the comments and suggestions of the members of X. Hou’s thesis advisory committee.
Affiliations: From the Program in Neuroscience, University of Mississippi Medical Center, Jackson, MS, USA (Hou, Wang); the Department of Pathology, University of Mississippi Medical Center, Jackson, MS, USA (Adeosun, Zhao, Zheng, Reddy, Wang); the Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, USA (Wang); the Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, MS, USA (Wang); the Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA (Mosley); the Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, Ont., Canada (Meyer); the Basic Medical College of Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang Province, China (Zhao); and the College of Health & Biomedicine, Victoria University, Melbourne, Australia (Su).
Competing interests: J. Meyer reports grants from Janssen, outside the submitted work. In addition, he has patents on a brain marker and blood markers of MAO-A for predicting mood disorder and on a dietary supplement to prevent postpartum depression and sad mood during high MAO-A states. No other competing interests declared.
Contributors: T. Mosley and J.M. Wang designed the study. X. Hou, S.O. Adeosun, X. Zhao, R. Hill, B. Zheng and R. Reddy acquired the data, which X. Hou, S.O. Adeosun, X. Zhao, R. Hill, B. Zheng, R. Reddy, X. Su, J. Meyer and J.M. Wang analyzed. X. Hou, S.O. Adeosun, X. Zhao, R. Hill and J.M. Wang wrote the article, which all authors reviewed. All authors approved the final version to be published and can certify that no other individuals not listed as authors have made substantial contributions to the paper.
Correspondence to: J. Wang, Department of Pathology, University of Mississippi Medical Center, 2500 North State St, Jackson, MS 39216; firstname.lastname@example.org