Thioredoxin interacting protein mediates corticosterone-induced depressive-like behavior in male mice

Chronic stress is a major risk factor for depression and other psychiatric disorders. Chronic treatment with stress hormone corticosterone (CORT) has been found to induce oxidative damage and depressive-like behaviors in rodents. Thioredoxin (Trx) antioxidant system includes Trx, Trx reductase (TrxR) and Trx-interacting protein (Txnip), and plays an important role in regulating oxidative stress. Trx is an oxidoreductase and reverses protein oxidation, TrxR maintains Trx reducing activity, while Txnip is an endogenous inhibitor for Trx. In this study, we explored the role of Trx system in chronic CORT treatment-induced neuronal damage and depressive-like behaviors in mice. We found that although chronic CORT treatment had no effect on Trx and TrxR protein levels, this treatment increased Txnip protein levels in primary cultured mouse cerebral cortical neurons. We also found that CORT treatment reduced cAMP response element-binding protein (CREB) phosphorylation. Because CREB phosphorylation is important in promoting neuronal differentiation, we further analyzed the effect of CORT treatment on dendritic outgrowth. We found that CORT treatment decreased dendritic outgrowth in cultured neurons and knocking down Txnip gene reversed CORT-decreased dendritic outgrowth. We also found that treatment with CORT for 21 days induced depressive-like behaviors in mice but knocking down Txnip in medial frontal cortex prevented CORT-induced depressive-like behaviors. Our results suggest that upregulation of Txnip by CORT may inhibit Trx activity, leading to oxidative damage, and impairment in neuronal differentiation, contributing to the development of depression.