miR-30 Family miRNAs Mediate the Effect of Chronic Social Defeat Stress on Hippocampal Neurogenesis in Mouse Depression Model

Abstract

Depression is a debilitating psychiatric disorder with a high rate of relapse and a low rate of response to antidepressant treatment. There is a dearth of new antidepressants due to an incomplete understanding of the molecular mechanisms involved in its etiopathology. Chronic stress appears to be one of the foremost underlying causes of depression. Studies in animal models in the past decade have implicated epigenetic mechanisms in mediating the negative effects of chronic stressful events on the progression/manifestation of depression and other co-morbid neuropsychiatric disorders. However, non-coding RNAs, another layer of epigenetic regulation is relatively less studied in depression. Here, using the chronic social defeat stress (CSDS)-induced depression model, we hypothesized dysregulation in miRNA-mRNA networks in the neurogenic dentate gyrus (DG) region of male C57BL/6 mice. Among several dysregulated miRNAs identified via miRNA arrays, the most striking finding was the downregulation of miRNAs of the miR-30 family in stressed/defeated mice. To investigate miRNAs in the DG-resident neural stem/progenitor cells (NSCs/NPCs), we used the in vitro neurosphere culture, where proliferating NSCs/NPCs were subjected to differentiation. Among several differentially expressed miRNAs, we observed an upregulation of miR-30 family miRNAs upon differentiation. To search for the gene targets of these miRNAs, we performed gene arrays followed by bioinformatics analysis, miRNA manipulations and luciferase assays. Our results suggest that miR-30 family miRNAs mediate chronic stress-induced depression-like phenotype by altering hippocampal neurogenesis and neuroplasticity via controlling the epigenetic and transcription regulators such as Mll3 and Runx1 ; and cell signaling regulators like Socs3, Ppp3r1, Gpr125 , and Nrp1 .

MiR-124 and the Underlying Therapeutic Promise of Neurodegenerative Disorders

“…MiRs are small single-stranded RNAs of about 21-23 bases. They are produced by Dicer enzyme processing of about 70-90 singlestranded RNA precursors with a hairpin structure (Khandelwal et al, 2019). The first confirmed miRs were lin-4 and let-7 found in nematodes.…”

Serum Level of miR-1 and miR-155 as Potential Biomarkers of Stress-Resilience of NET-KO and SWR/J Mice

“…Another interesting miRNA identified in the present study is miR-30, which was downregulated following RS in the serum of WT mice but not in the NET-KO and SWR/J animals. The alterations in miR-30 level were also described after social defeat stress in the dentate gyrus of the C57BL/6 mice [37]. These results suggest that the abovementioned changes may be associated with the stress-susceptible phenotype of WT mice, while no change was found in the stress-resilient phenotypes, i.e., NET-KO and SWR/J mice.…”

Potential clinical value of circular RNAs as peripheral biomarkers for the diagnosis and treatment of major depressive disorder

“…In the circFKBP8-associated ceRNA network, blood miR-139 may be a potential diagnostic biomarker for MDD [74] and the miR-346 may be useful biomarkers for schizophrenia diagnosis [ 75 , 76 ]. Meanwhile, in the MBNL1-associated ceRNA network, previous studies [77] , [78] , [79] revealed that blood miR-320b/c, miR-17, and miR-30a were associated with depression and the miR-125b was associated with Alzheimer's disease. These evidence further supported the underlying association between these circRNAs and MDD.…”