PMID- 28544903 OWN - NLM STAT- MEDLINE DCOM- 20180403 LR - 20181113 IS - 1873-3360 (Electronic) IS - 0306-4530 (Print) IS - 0306-4530 (Linking) VI - 82 DP - 2017 Aug TI - Estrogen receptor beta deficiency impairs BDNF-5-HT(2A) signaling in the hippocampus of female brain: A possible mechanism for menopausal depression. PG - 107-116 LID - S0306-4530(16)30939-8 [pii] LID - 10.1016/j.psyneuen.2017.05.016 [doi] AB - Depression currently affects 350 million people worldwide and 19 million Americans each year. Women are 2.5 times more likely to experience major depression than men, with some women appearing to be at a heightened risk during the menopausal transition. Estrogen signaling has been implicated in the pathophysiology of mood disorders including depression; however, the underlying mechanisms are poorly understood. In this study, the role of estrogen receptor (ER) subtypes, ERalpha and ERbeta, in the regulation of brain-derived neurotrophic factor (BDNF) and serotonin (5-HT) signaling was investigated; two pathways that have been hypothesized to be interrelated in the etiology of depression. The analyses in ERalpha(-/-) and ERbeta(-/-) mouse models demonstrated that BDNF was significantly downregulated in ERbeta(-/-) but not ERalpha(-/-) mice, and the ERbeta(-/-)-mediated effect was brain-region specific. A 40% reduction in BDNF protein expression was found in the hippocampus of ERbeta(-/-) mice; in contrast, the changes in BDNF were at a much smaller magnitude and insignificant in the cortex and hypothalamus. Further analyses in primary hippocampal neurons indicated that ERbeta agonism significantly enhanced BDNF/TrkB signaling and the downtream cascades involved in synaptic plasticity. Subsequent study in ERbeta mutant rat models demonstrated that disruption of ERbeta was associated with a significantly elevated level of 5-HT(2A) but not 5-HT(1A) in rat hippocampus, indicating ERbeta negatively regulates 5-HT(2A). Additional analyses in primary neuronal cultures revealed a significant association between BDNF and 5-HT(2A) pathways, and the data showed that TrkB activation downregulated 5-HT(2A) whereas activation of 5-HT(2A) had no effect on BDNF, suggesting that BDNF/TrkB is an upstream regulator of the 5-HT(2A) pathway. Collectively, these findings implicate that the disruption in estrogen homeostasis during menopause leads to dysregulation of BDNF-5-HT(2A) signaling and weakened synaptic plasticity, which together predispose the brain to a vulnerable state for depression. Timely intervention with an ERbeta-targeted modulator could potentially attenuate this susceptibility and reduce the risk or ameliorate the clinical manifestation of this brain disorder. CI - Copyright (c) 2017 Elsevier Ltd. All rights reserved. FAU - Chhibber, Anindit AU - Chhibber A AD - Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, KS, USA. FAU - Woody, Sarah K AU - Woody SK AD - Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, KS, USA. FAU - Karim Rumi, M A AU - Karim Rumi MA AD - Institute for Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, KS, USA. FAU - Soares, Michael J AU - Soares MJ AD - Institute for Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, KS, USA. FAU - Zhao, Liqin AU - Zhao L AD - Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, KS, USA; Neuroscience Graduate Program, University of Kansas, Lawrence, KS, USA. Electronic address: lzhao@ku.edu. LA - eng GR - P20 GM103418/GM/NIGMS NIH HHS/United States GR - R21 OD010478/OD/NIH HHS/United States PT - Journal Article DEP - 20170518 PL - England TA - Psychoneuroendocrinology JT - Psychoneuroendocrinology JID - 7612148 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Estrogen Receptor beta) RN - 0 (Membrane Glycoproteins) RN - 0 (Receptor, Serotonin, 5-HT2A) RN - 0 (Serotonin 5-HT2 Receptor Agonists) RN - 112692-38-3 (Receptor, Serotonin, 5-HT1A) RN - 333DO1RDJY (Serotonin) RN - EC 2.7.10.1 (Receptor, trkB) RN - EC 2.7.10.1 (tropomyosin-related kinase-B, human) SB - IM MH - Animals MH - Brain/metabolism MH - Brain-Derived Neurotrophic Factor/*metabolism/physiology MH - Cerebral Cortex/metabolism MH - Depression/etiology/physiopathology MH - Depressive Disorder, Major/metabolism MH - Estrogen Receptor beta/genetics/*metabolism MH - Female MH - Hippocampus/metabolism/pathology MH - Membrane Glycoproteins/metabolism MH - Menopause/*metabolism MH - Mice MH - Neurons/metabolism MH - Primary Cell Culture MH - Rats MH - Receptor, Serotonin, 5-HT1A/metabolism MH - Receptor, Serotonin, 5-HT2A/*metabolism MH - Receptor, trkB/metabolism MH - Serotonin/metabolism MH - Serotonin 5-HT2 Receptor Agonists/metabolism MH - Temporal Lobe/metabolism PMC - PMC5523821 MID - NIHMS878847 OTO - NOTNLM OT - 5-HT(1A) OT - 5-HT(2A) OT - Brain-derived neurotrophic factor (BDNF) OT - Estrogen receptor beta (ERbeta) OT - Hippocampus OT - Menopausal depression EDAT- 2017/05/26 06:00 MHDA- 2018/04/04 06:00 PMCR- 2018/08/01 CRDT- 2017/05/26 06:00 PHST- 2016/11/24 00:00 [received] PHST- 2017/05/15 00:00 [revised] PHST- 2017/05/16 00:00 [accepted] PHST- 2017/05/26 06:00 [pubmed] PHST- 2018/04/04 06:00 [medline] PHST- 2017/05/26 06:00 [entrez] PHST- 2018/08/01 00:00 [pmc-release] AID - S0306-4530(16)30939-8 [pii] AID - 10.1016/j.psyneuen.2017.05.016 [doi] PST - ppublish SO - Psychoneuroendocrinology. 2017 Aug;82:107-116. doi: 10.1016/j.psyneuen.2017.05.016. Epub 2017 May 18.