Article

FSHR ablation induces depression-like behaviors

Wen-kai Bi1,2,3,4, Shan-shan Shao1,2,3,4, Zhi-wei Li5, Yong-wei Ruan5, Si-si Luan1,2,3,4, Zhen-hua Dong6, Jing Wang1,2,3,4, Shan-shan Wu1,2,3,4, Tian Guo1,2,3,4, Shi-zhan Ma1,2,3,4, Ling Gao1,2,3, Jia-jun Zhao1,2,3,7, Zhao He1,2,3,4,7
1 Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Ji-nan 250000, China
2 Shandong Provincial Key Laboratory of Endocrinology and Lipid Metabolism, Ji-nan 250000, China
3 Institute of Endocrinology and Metabolism, Shandong Academy of Clinical Medicine, Ji-nan 250000, China
4 School of Medicine, Shandong University, Ji-nan 250000, China
5 Department of Breast Thyroid Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Ji-nan 250000, China
6 Department of Endocrinology, Ji-nan Central Hospital Affiliated to Shandong University, Ji-nan 250000, China
7 Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University and Shandong Academy of Medical Sciences, Ji-nan 250000, China
Correspondence to: Ling Gao: linggao@sdu.edu.cn, Jia-jun Zhao: jjzhao@sdu.edu.cn, Zhao He: zhaohe7711@qq.com,
DOI: 10.1038/s41401-020-0384-8
Received: 15 October 2019
Accepted: 19 February 2020
Advance online: 18 March 2020

Abstract

Alteration in reproductive hormones profile is associated with the increasing risk of menopausal depression in women. Serum follicle-stimulating hormone (FSH) level is changed during the menopause transition, while the effect of FSH on menopausal depression has remained undefined. In this study we investigated whether or how FSH affected menopausal depression in postmenopausal (ovariectomized) FSHR knockout mice (Fshr−/−). We found that Fshr−/− mice displayed aggravated depression-like behaviors, accompanied by severe oxidative stress in the whole brain, resulted from significantly reduced glutamate cysteine ligase modifier subunit (GCLm) in glutathione synthesis and glucose-6-phosphate dehydrogenase (G6PD) in NADP/NADPH transition. Importantly, administration of ROS scavenger N-acetyl cysteine (NAC, 150 mg · kg−1 · d−1, i.p. for 12 weeks) attenuated the depression-like behaviors of Fshr−/− mice. Consistent with these in vivo experiment results, we found that pretreatment with FSH (50, 100 ng/mL) dose-dependently increased protein levels of GCLm and G6PD, and decreased the ROS production in N2a mouse neuroblastoma cells. These findings demonstrate that FSH signaling is involved in pathogenesis of menopausal depression, and likely to maintain the redox-optimized ROS balance in neurons.
Keywords: FSH; aging; antioxidants; metabolism; ROS; depression

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