Suppression of miR-146a-5p/SMAD4 signaling pathway ameliorates hippocampal neuronal injury caused by chronic stress

Abstract

Chronic stress-induced depression is a prevalent neuropsychiatric disease with high recurrence and suicide rate, which brings a heavy burden to society. However, the cure rate for depression remains comparatively low in clinical practice, partially due to the unclear pathogenesis. The present study showed that increased expression of miR-146a-5p within hippocampus may lead to depression-like behaviors in rats, accompanied by loss of neuronal dendritic spines, decreased expression of synaptic-related proteins, enhanced neuroinflammatory response and suppressed neurogenesis, effects which appear to be mediated by the SMAD4 signaling pathway. However, knock-down of miR-146a-5p within the hippocampal dentate gyrus (DG) regions of depressed rats significantly increased the expression of SMAD4, as well as restored the neural deterioration, which consequently ameliorates the depression-like behaviors in rats. In summary, these results suggest that chronic unpredicted mild stress (CUMS) may cause neuronal injury and neurogenesis deficits via up-regulating miR-146a-5p/SMAD4 pathway within the hippocampus, which provides the potential therapeutic target for the treatment of depression.