MiR-218: A Molecular Switch and Potential Biomarker of Susceptibility to Stress

Abstract

Circulating miR-218 as biomarker of stress susceptibility 2 ABSTRACT Low miR-218 expression in the medial prefrontal cortex (mPFC) is a consistent trait of depression.Here we assessed whether miR-218 in the mPFC confers resilience or susceptibility to depression-like behaviors in adult mice, using the chronic social defeat stress (CSDS) model of depression. We also investigated whether stress-induced variations of miR-218 expression in the mPFC can be detected in blood. We find that downregulation of miR-218 in the mPFC increases susceptibility to a single session of social defeat, whereas overexpression of miR-218 selectively in mPFC pyramidal neurons promotes resilience to CSDS and prevents stress-induced morphological alterations to those neurons. After CSDS, susceptible mice have low levels of miR-218 in the blood as compared to control or resilient groups. We show further that up-and downregulation of miR-218 levels specifically in the mPFC correlates with miR-218 expression in blood. Our results suggest that miR-218 in the adult mPFC might function as a molecular switch that determines susceptibility versus resilience to chronic stress, and that stress-induced variations in mPFC levels of miR-218 could be detected in blood. We propose that blood expression of miR-218 might serve as potential readout of vulnerability to stress and as a proxy of mPFC function.Circulating miR-218 as biomarker of stress susceptibility 3

Region-specific microRNA alterations in marmosets carrying SLC6A4 polymorphisms are associated with anxiety-like behavior

“…We found no difference across haplotypes in the expression of any low probability target or reference targets in area 32 (Suppl. sequences for miR-9-5p, let7-5p and miR-190, the observed downregulation was moderate, in agreement with the contention that miRNAs fine-tune gene expression [33,34]. As expected, levels of DCC and those of miR-9-5p, let7-5p and miR-190 miRNAs were inversely correlated.…”

“…Second, as previously shown, miRNA-dependent fine-tuning of specific targets has been consistently involved in the pathophysiology of stressrelated disorders [22,44]. Our findings pinpoint the therapeutic potential of DCC, a well-established risk factor for depression [22,34,45]. Previous work demonstrated that DCC expression is under the control of miR-218 [33,34].…”

“…Our findings pinpoint the therapeutic potential of DCC, a well-established risk factor for depression [22,34,45]. Previous work demonstrated that DCC expression is under the control of miR-218 [33,34]. Although we could not observe any difference in miR-218 associated to SLC6A4 variants (Suppl.…”

Reviewing the Role of the Endocannabinoid System in the Pathophysiology of Depression

“…In fact, several factors have been long associated with the development of MDD including environmental, but also genetic (Nestler et al, 2002). For example, adverse life events, like early-life stress, are considered one of the greatest risk factors (Torres-Berrío et al, 2019;Nelson and Gabard-Durnam 2020). Alternatively, some genetic influences have also been associated with the heritability of MDD, which is estimated to be approximately 38% (Kendler et al, 2006).…”