Effect of Toll-like receptor 4 on depressive-like behaviors induced by chronic social defeat stress

Introduction: A growing body of evidence suggests that stress is an important factor in depression, and pro-inflammatory cytokines contribute to the occurrence and development of depression in both animal models and human patients. Toll-like Receptor 4 (TLR4) has been shown to be a key innate immune pattern recognition receptor involved in the regulation of stress responses and inflammation. However, the exact effects of TLR4 on depressive-like behaviors induced by chronic social defeat stress (CSDS) are not known.

Methods: In this study, the effects of TLR4 on depressive-like behaviors were investigated in an animal model of depression induced by CSDS. The depressive-like behaviors were assessed by forced swimming test (FST), social interaction test (SIT), and light-dark box test (LDT). The protein expressions of TLR4 and tumor necrosis factor-α (TNF-α) in the hippocampus were measured using Western blotting.

Results: We found that CSDS increased TLR4 protein levels in the hippocampus and induced behavioral despair in FST, social avoidance in SIT, and anxiety-like behavior in LDT. Fluoxetine normalized the increased expression of TLR4 and reversed behavioral despair, social avoidance, as well as anxiety-like behavior induced by CSDS. However, directly blocking TLR4, by using either TLR4 Inhibitor TAK-242 or knockout of TLR4, only inhibited behavioral despair, but not social avoidance or anxiety-like behavior induced by CSDS.

Conclusions: These results demonstrate a specific modulating role of TLR4 in behavioral despair induced by CSDS and suggest that TAK-242 may be a beneficial treatment for patients with behavioral despair.