miR-138 Increases Depressive-Like Behaviors by Targeting SIRT1 in Hippocampus

Abstract

Cuixia Li,1 Feng Wang,2 Pei Miao,1 Libo Yan,1 Silin Liu,1 Xian Wang,1 Zuolin Jin,1 Zexu Gu1 1State 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; 2Department of Stomatology, 546 Hospital of PLA, Malan City, Xinjiang Province 841200, People’s Republic of ChinaCorrespondence: Zuolin Jin; Zexu GuState 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 ChinaEmail [email protected]; [email protected]: 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.Methods: 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.Results: 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.Conclusion: 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.Keywords: depression, microRNA, miR-138, SIRT1, chronic unpredictable mild stress, CUMS

Keywords

• depression
• microrna
• mir-138
• sirt1
• chronic unpredictable mild stress (cums)