Alterations of microRNA-124 expression in peripheral blood mononuclear cells in pre- and post-treatment patients with major depressive disorder

Abstract

Recently, increasing evidence has indicated that dysfunction of microRNA-124 (miR-124) might be involved in the pathophysiology and treatment of major depressive disorder (MDD) in some animal models of depression. However, the role of miR-124 in MDD patients remains unclear. The objective of this study was to investigate whether the miR-124 expression levels in peripheral blood mononuclear cells (PBMCs) were associated with MDD and to evaluate the effects of antidepressant treatment on miR-124 levels. Quantitative real-time PCR was applied to detect miR-124 expression in 32 pre- and post-treatment MDD patients and 30 healthy controls. Our results showed that expression levels of miR-124 from PBMCs in MDD patients were significantly higher than those in healthy controls (p < 0.001), and that the area under the curve of miR-124 from ROC analysis was 0.762 with a sensitivity of 83.33% and specificity of 66.67% in distinguishing MDD patients from healthy controls. In addition, the expression levels of miR-124 were significantly down-regulated after eight weeks of treatment (p < 0.001). MiRNA target gene prediction and functional annotation analysis indicated that altered miR-124 was involved in affecting some important biological processes and pathways related to MDD. These results provide new information on miR-124 involvement in the biological alterations of MDD and in antidepressant effects.

Introduction

Despite a few decades of unremitting efforts, the pathogenesis of major depressive disorder (MDD) and the mechanisms of antidepressant treatment have not been elucidated. In recent years, the neurotrophic hypothesis of depression has increasingly attracted the attention of researchers. Briefly, this hypothesis states that the impairment of synaptic plasticity, particularly in the hippocampus, may be a core factor in the pathophysiology of depression (Duman and Li, 2012).

MiRNAs are 22–25 nucleotide non-coding RNAs that can negatively regulate gene expression by repressing mRNA translation and/or mediating cleavage of mRNAs at the post-transcriptional level (Flynt and Lai, 2008). MiRNAs are abundant in the brain, and they have been found to play a critical role in several aspects of brain function, particularly neurogenesis, neuronal plasticity, and neuronal development (Kosik, 2006 and Zeng, 2009). Emerging evidence has demonstrated that dysregulation of miRNA expression occurs in animal models of depression (Cao et al., 2013), in the post-mortem brain tissue of depressed subjects (Lopez et al., 2014 and Smalheiser et al., 2012, Smalheiser et al., 2014), and in the CSF and the peripheral blood of depressed patients (Belzeaux et al., 2012, Fan et al., 2014, Li et al., 2013 and Wan et al., 2015). Moreover, it has been shown that selective serotonin reuptake inhibitors, other types of antidepressants, and other physical treatment such as electroconvulsive therapy, can modify aberrant miRNA expression and their downstream targets (Belzeaux et al., 2012, Bocchio-Chiavetto et al., 2013, Lopez et al., 2014 and Ryan et al., 2013).

Among miRNAs, miR-124 is the most abundant miRNA in the brain (Lagos-Quintana et al., 2002). MiR-124 is derived from three independent genes (miR-124-1 also known as miR-124a, miR-124-2, and miR-124-3) that all produce the same mature miRNA. It has been reported that miR-124 can regulate adult neurogenesis, promote neuronal differentiation, and contribute to synaptic plasticity in vivo (Cheng et al., 2009 and Makeyev et al., 2007). In a previous study, miR-124 expression levels were found to be increased in the hippocampus of chronic unpredictable stress induced depression model rats (Cao et al., 2013). Similarly, another recent study has shown that overexpression of miR124a contributes to chronic social stress-induced depression in rats. Moreover, this study also found that knockdown of miR124a expression by lentivirus mediated siRNA expression vector (LV-siR124a) in the hippocampus of rats had an antidepressant-like effect (Bahi et al., 2014). In this situation, we could speculate that miR-124 is associated with the pathophysiology of depression and is a potential target for antidepressant treatments.

To date, though there have been some studies on the alteration of miR-124 levels in animal models of depression, few clinical studies have investigated the relationship between the levels of miR-124 in PBMCs and MDD patients. In addition, there are few data available yet pertaining to the effect of antidepressants on miR-124 levels in PBMCs in MDD patients. Therefore, in this study, we combined a cross-sectional and longitudinal naturalistic observational design to determine the possible alterations of miR-124 levels of PBMCs in MDD patients prior to treatment by comparing those in healthy controls and to further investigate whether antidepressant treatment can change the miR-124 levels in MDD patients.

On these bases, we sought to explore the potential role of miR-124 in biological alterations of MDD and in antidepressant effects. Putative target genes of the miR-124 and their possible functions and biological mechanisms were investigated using bioinformatics tools.