2. Academic Validation
  3. Transcription Factor TWIST1 Integrates Dendritic Remodeling and Chronic Stress to Promote Depressive-like Behaviors

Transcription Factor TWIST1 Integrates Dendritic Remodeling and Chronic Stress to Promote Depressive-like Behaviors

  • Biol Psychiatry. 2021 Mar 15;89(6):615-626. doi: 10.1016/j.biopsych.2020.09.003.
Jin-Gang He 1,  Hai-Yun Zhou 1,  Shi-Ge Xue 1,  Jia-Jing Lu 1,  Jun-Feng Xu 1,  Bin Zhou 1,  Zhuang-Li Hu 2,  Peng-Fei Wu 2,  Li-Hong Long 2,  Lan Ni 3,  You Jin 3,  Fang Wang 4,  Jian-Guo Chen 5
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China; Research Center for Depression, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
  • 2 Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China; Research Center for Depression, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China; Key Laboratory for Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, People's Republic of China.
  • 3 Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
  • 4 Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China; Research Center for Depression, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China; Laboratory of Neuropsychiatric Diseases, Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, People's Republic of China; Key Laboratory for Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, People's Republic of China; Key Laboratory of Neurological Diseases, Ministry of Education of China, Wuhan, People's Republic of China. Electronic address: wangfangtj0322@163.com.
  • 5 Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China; Research Center for Depression, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China; Laboratory of Neuropsychiatric Diseases, Institute of Brain Research, Huazhong University of Science and Technology, Wuhan, People's Republic of China; Key Laboratory for Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, People's Republic of China; Key Laboratory of Neurological Diseases, Ministry of Education of China, Wuhan, People's Republic of China. Electronic address: chenj@mails.tjmu.edu.cn.
PMID: 33190845 DOI: 10.1016/j.biopsych.2020.09.003
Abstract

Background: Deficiency in neuronal structural plasticity is involved in the development of major depressive disorder. TWIST1, a helix-loop-helix transcription factor that is essential for morphogenesis and organogenesis, is normally expressed at low levels in mature neurons. However, it is poorly understood what role TWIST1 plays in the brain and whether it is involved in the pathophysiology of depression.

Methods: Depressive-like behaviors in C57BL/6J mice were developed by chronic social defeat stress. Genetic and pharmacological approaches were used to investigate the role of the TWIST1-miR-214-PPAR-δ signaling pathway in depressive-like behaviors. Molecular biological and morphological studies were performed to define the molecular mechanisms downstream of TWIST1.

Results: The expression of TWIST1 was positively correlated with depressive behaviors in humans and mice. Chronic stress elevated TWIST1 expression in the medial prefrontal cortex of mice, which was reversed by fluoxetine treatment. While the overexpression of TWIST1 increased susceptibility to stress, the knockdown of TWIST1 prevented the defective morphogenesis of dendrites of pyramidal neurons in layer II/III of the medial prefrontal cortex and alleviated depressive-like behaviors. Mechanistically, this prodepressant property of TWIST1 was mediated, at least in part, through the repression of miR-214-PPAR-δ signaling and mitochondrial function, which was also mimicked by genetic and pharmacological inhibition of PPAR-δ.

Conclusions: These results suggest that TWIST1 in the medial prefrontal cortex mediates chronic stress-induced dendritic remodeling and facilitates the occurrence of depressive-like behavior, providing new information for developing drug targets for depression therapy.

Keywords

Dendritic remodeling; Depressive-like behaviors; Medial prefrontal cortex; Peroxisome proliferator–activated receptor-δ; Stress; TWIST1.

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