Li Cuixia, Wang Feng, Miao Pei, Yan Libo, Liu Silin, Wang Xian, Jin Zuolin, Gu Zexu
State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontics, School of Stomatology, the Fourth Military Medical University, Xian 710032, People's Republic of China.
Department of Stomatology, 546 Hospital of PLA, Malan City, Xinjiang Province 841200, People's Republic of China.
Neuropsychiatr Dis Treat. 2020 Apr 9;16:949-957. doi: 10.2147/NDT.S237558. eCollection 2020.
Major depressive disorder (MDD) is a serious and common mood disorder with unknown etiology. Emerging evidence has demonstrated the critical roles of SIRT1 and microRNAs (miRNAs) in the progression of MDD. However, the underlying molecular mechanisms remain to be fully understood.
In the present study, the expression level of miR-138 and SIRT1 were analyzed by RT-PCR or Western blotting in a chronic unpredictable mild stress (CUMS) model. The depressive-like behaviors were analyzed by forced swimming test (FST) and sucrose preference test (SPT) in mice injected with miR-138 and SIRT1 overexpression lentivirus. The luciferase reporter assay was used to assess the direct regulation of miR-138 on SIRT1 expression.
The upregulation of miR-138 was found in the hippocampus of the CUMS mice and correlated with decreased SIRT1 expression. C57BL/6J mice treated with SIRT1- and miR-138-expressing (miR-138) lentivirus showed increased depressive-like behaviors. In contrast, SIRT1 or si-miR-138 lentivirus treated C57BL/6J mice showed decreased depressive-like behaviors. Moreover, the Sirt1/PGC-1α/FNDC5/BDNF pathway was downregulated following miR-138 overexpression and increased upon miR-138 knockdown in hippocampus in CUMS mice and cultured primary neuronal cells. Mechanistically, luciferase reporter assay demonstrated that SIRT1 gene was a downstream transcriptional target of miR-138.
Our data demonstrated the regulation role of miR-138 on SIRT1 gene expression, miR-138 increased depressive-like behaviors by regulating SIRT1 expression in hippocampus.
重度抑郁症（MDD）是一种严重且常见的情绪障碍，病因不明。新出现的证据表明，SIRT1和微小RNA（miRNA）在MDD的进展中起关键作用。然而，其潜在的分子机制仍有待充分了解。
在本研究中，通过逆转录聚合酶链反应（RT-PCR）或蛋白质免疫印迹法分析慢性不可预测轻度应激（CUMS）模型中miR-138和SIRT1的表达水平。对注射了miR-138和SIRT1过表达慢病毒的小鼠，通过强迫游泳试验（FST）和蔗糖偏好试验（SPT）分析其抑郁样行为。采用荧光素酶报告基因检测法评估miR-138对SIRT1表达的直接调控作用。
在CUMS小鼠的海马体中发现miR-138上调，且与SIRT1表达降低相关。用表达SIRT1和miR-138的慢病毒处理的C57BL/6J小鼠表现出更多的抑郁样行为。相反，用SIRT1或si-miR-138慢病毒处理的C57BL/6J小鼠表现出较少的抑郁样行为。此外，在CUMS小鼠和原代培养神经元细胞的海马体中，miR-138过表达后Sirt1/PGC-1α/FNDC5/BDNF通路下调，而miR-138敲低后该通路上调。机制上，荧光素酶报告基因检测表明SIRT1基因是miR-138的下游转录靶点。
我们的数据证明了miR-138对SIRT1基因表达的调控作用，miR-138通过调节海马体中SIRT1的表达增加抑郁样行为。
