2. Academic Validation
  3. Androgens alleviate the depression-like phenotype in female mice by inhibiting AVPR1a in the hippocampal brain region

Androgens alleviate the depression-like phenotype in female mice by inhibiting AVPR1a in the hippocampal brain region

  • Mol Med. 2025 May 29;31(1):210. doi: 10.1186/s10020-025-01272-9.
Shimin Ren # 1 2,  Xian Wang # 1 2,  Xueying Huang # 3,  Liyang Chen 4,  Bing Zhang 5,  Yang Li 6 7,  Xin Huang 8
Affiliations

Affiliations

  • 1 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China.
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 3 Shanghai Key Laboratory of Maternal-Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 201204, China.
  • 4 Key Laboratory of Environmental Medical Engineering and Education Ministry, School of Public Health, Southeast University, Nanjing, Jiangsu, 210009, China.
  • 5 Shanghai Key Laboratory of Maternal-Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 201204, China. bingozzz@126.com.
  • 6 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, China. liyang@simm.ac.cn.
  • 7 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. liyang@simm.ac.cn.
  • 8 Reproductive Medical Center, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200082, China. huangxin@xinhuamed.com.cn.
  • # Contributed equally.
PMID: 40437391 DOI: 10.1186/s10020-025-01272-9
Abstract

Background: The prevalence of depression in women is approximately twice that in men. Differences in androgens levels between men and women, due to gonadal differences, may be associated with the development of depression, although the underlying mechanisms are not well understood.

Methods: We evaluated the depressive phenotypes of female mice following low-dose androgen treatment using a variety of behavioral and in vivo electrophysiological experiments. The mRNA profile of hippocampal tissues from female mice treated with dehydroepiandrosterone (DHEA) was constructed through RNA Sequencing (RNA-seq). GO and KEGG pathway analyses were performed on the differentially expressed genes. The expression changes of candidate differential genes were verified in hippocampal tissues by quantitative Real-Time PCR and western blotting. Moreover, the mechanism of action of the DHEA-regulated differential gene (Avpr1a), which is involved in the neuroactive ligand-receptor interaction pathway, was determined in vitro.

Results: Chronic DHEA treatment resulted in a distinct antidepressant phenotype and significantly enhanced neuronal excitability of the ventral hippocampal region of female mice. RNA-seq identified the crucial differentially expressed gene, Avpr1a. In vitro experiments showed that DHEA reduced levels of the AVP system. Additionally, ChIP-PCR experiments revealed that Avpr1a directly targets Androgen Receptor (AR). Cell function experiments demonstrated that DHEA can inhibit AVPR1a expression through AR in a dose-dependent manner, and this effect can be reversed by the Androgen Receptor antagonist (Flutamide).

Conclusion: Androgens (DHEA) exert antidepressant effects by inhibiting the binding of Avpr1a to AR. The Avpr1a gene may serve as a new target for the treatment of depression in women.

Keywords

AVPR1a; Androgen receptors; DHEA; Depression; Female; Hippocampus.

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