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
复制标题
转录因子 TWIST1 整合树突重塑和慢性压力以促进抑郁样行为。
DOI：
10.1016/j.biopsych.2020.09.003
复制
发表时间：
2021-02-15
影响因子：
10.6
通讯作者：
Chen, Jian-Guo
中科院分区：
文献类型：
--
作者：
He, Jin-Gang;Zhou, Hai-Yun;Chen, Jian-Guo
背景：神经元结构可塑性的缺陷与重度抑郁症的发展有关。 TWIST1 是一种螺旋-环-螺旋转录因子，对于形态发生和器官发生至关重要，通常在成熟神经元中低水平表达。然而，人们对TWIST1在大脑中的作用以及它是否参与抑郁症的病理生理学知之甚少。方法：C57BL/6J小鼠的抑郁样行为是由长期的社会失败压力产生的。使用遗传和药理学方法研究 TWIST1-miR-214-PPAR-delta 信号通路在抑郁样行为中的作用。通过分子生物学和形态学研究来确定 TWIST1 下游的分子机制。结果：TWIST1 的表达与人类和小鼠的抑郁行为呈正相关。慢性应激导致小鼠内侧前额叶皮质中 TWIST1 表达升高，氟西汀治疗可逆转这种情况。虽然 TWIST1 的过度表达增加了对压力的敏感性，但 TWIST1 的敲低可以防止内侧前额叶皮层 II/III 层锥体神经元树突的缺陷形态发生，并减轻抑郁样行为。从机制上讲，TWIST1 的这种促抑郁特性至少部分是通过抑制 miR-214-PPAR-delta 信号传导和线粒体功能来介导的，这也通过 PPAR-delta 的遗传和药理学抑制来模拟。 结论：这些结果表明内侧前额叶皮层中的 TWIST1 介导慢性应激诱导的树突重塑并促进抑郁样行为的发生，为开发药物提供新信息抑郁症治疗的目标。
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-delta 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-delta signaling and mitochondrial function, which was also mimicked by genetic and pharmacological inhibition of PPAR-delta.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.