Zhang Xiaonan, Yan Wei, Xue Ying, Xu Hong, Li Jinying, Zhao Ziwei, Sun Ye, Wang Yanfang, He Jiaqian, Huang Yuyue, Yu Deqin, Xiao Zhaoyang, Yin Shengming
College of Basic Medical Sciences, Dalian Medical University, Dalian, Liaoning, China.
National and Local Joint Engineering Research Center for Drug Research and Development of Neurodegenerative Diseases, Dalian, Liaoning, China.
Neurobiol Stress. 2021 Sep 11;15:100396. doi: 10.1016/j.ynstr.2021.100396. eCollection 2021 Nov.
Adenosine deaminase acting on RNA1 (ADAR1) is a newly discovered epigenetic molecule marker that is sensitive to environmental stressors. A recent study has demonstrated that ADAR1 affects BDNF expression via miR-432 and is involved in antidepressant action. However, the detailed molecular mechanism is still unclear. We have uncovered a new molecular mechanism showing the involvement of miR-432 and circ_0000418 in mediating the antidepressant action of ADAR1. We demonstrate that the ADAR1 inducer (IFN-γ) alleviates the depressive-like behaviors of BALB/c mice treated with chronic unpredictable stress (CUS) exposure. Moreover, both in vivo and in vitro studies show that ADAR1 differently impacts miR-432 and circ_0000418 expressions. Furthermore, the in vitro results demonstrate that circ_0000418 oppositely affects BDNF expression. Together, our results indicate that ADAR1 affects CUS-induced depressive-like behavior and BDNF expression by acting on miR-432 and circ_0000418. Elucidation of this new molecular mechanism will not only provide insights into further understanding the important role of ADAR1 in stress-induced depressive-like behavior but also suggest a potential therapeutic strategy for developing novel anti-depressive drugs.
作用于RNA1的腺苷脱氨酶（ADAR1）是一种新发现的对环境应激源敏感的表观遗传分子标志物。最近的一项研究表明，ADAR1通过miR-432影响脑源性神经营养因子（BDNF）的表达，并参与抗抑郁作用。然而，具体的分子机制仍不清楚。我们发现了一种新的分子机制，表明miR-432和circ_0000418参与介导ADAR1的抗抑郁作用。我们证明，ADAR1诱导剂（干扰素-γ）可减轻经慢性不可预测应激（CUS）处理的BALB/c小鼠的抑郁样行为。此外，体内和体外研究均表明，ADAR1对miR-432和circ_0000418的表达有不同影响。此外，体外实验结果表明，circ_0000418对BDNF表达有相反影响。总之，我们的结果表明，ADAR1通过作用于miR-432和circ_0000418影响CUS诱导的抑郁样行为和BDNF表达。阐明这一新的分子机制不仅有助于进一步理解ADAR1在应激诱导的抑郁样行为中的重要作用，还为开发新型抗抑郁药物提供了潜在的治疗策略。
