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.
Highlights
Depression is one of the major debilitating mental disorders that affect a significant portion of the global population
Molecular investigations using animal models of depression suggest that being subjected to stress for a prolonged period affects gene expression and causes an alteration in neuronal morphology and functional biology, resulting in depression, anxiety, and related mood disorders
The mood or affective disorders have been shown to be associated with long-term or persistent changes in hippocampal remodeling and/or neuroplasticity, which are correlated with the attenuation in dentate gyrus (DG) neurogenesis
Summary
Depression is one of the major debilitating mental disorders that affect a significant portion of the global population. Prime attention has been given to the changes in histone modifications and DNA methylation, which in turn, alter the expression of critical genes affecting the neural circuitry involved (Uchida et al, 2018; Kuehner et al, 2019). There is another layer of gene regulation, mediated by the non-coding RNAs, which is less explored in the context of depression and related mood disorders
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