miR-182 mediated the inhibitory effects of NF-κB on the GPR39/CREB/BDNF pathway in the hippocampus of mice with depressive-like behaviors

Background: Chronic stress is one of the most important causes of depression, accompanied by neuminflammation and hippocampal injuries. Long-term elevation of glucocorticoid leads to activation of NF-kappa B and inhibition of GPR39/CREB/BDNF pathway, which is pivotal for neuroprotection and neumgenesis. The present study thus was designed to determine the relationship between NF-kappa B and GPR39/CREB/BDNF pathway. Methods: Depressive-like behaviors were induced by chronic unpredictable mild stress (GUMS) and chronic restraint stress (CRS) in mice. Corticosterone, inflammatory cytokines, and GPR39/CREB/BDNF pathway were determined by ELISA and Western Blot assays. The activation of NF-kappa B and inhibition of GPR39 were connected by bioinformatic analysis and experimentally validated in hippocampus cells by knock-in and knock-down techniques. Results: GUMS and CRS led to an elevation of serum corticosterone and depressive-like behaviors in mice, with activation of NF-kappa B subunit p65 in the hippocampus and elevations of TNF alpha and IL-6. The expression of GPR39/ CREB/BDNF pathway in the hippocampus was inhibited. Bioinformatic analysis revealed that four miRNAs, miR96, miR-143, miR-150, and miR-182, were potentially transcribed by NF-kappa B and bound with GPR39 mRNA. NF-kappa B overexpression increased miR-182 expression and decreased GPR39 expression in hippocampus cells. Its inhibitor led to reverse effects. miR-182 mimics or inhibitors also regulated GPR39 expression in hippocampus cells and more importantly, blocked the regulation of NF-kappa B on GPR39. Conclusions: The results suggested that activation of NF-kappa B inhibited GPR39/CREB/BDNF pathway through increasing miR-182 in chronic stress-induced depressive-like behaviors. The negative-regulation features of miRNAs might be important for neuroinflammation-induced inhibition of neurofunction in depression.

Automated summary

The study found that activation of NF-kappa B inhibited the GPR39/CREB/BDNF pathway by increasing miR-182 in chronic stress-induced depressive-like behaviors. The negative-regulation features of miRNAs may play an important role in the inhibition of neurofunction induced by neuroinflammation in depression.