Stress induces behavioral disorders by promoting microglial phagocytosis via decreasing neuronal Dkk3

Microglia play an important role in the central nervous system, particularly with regard to altering synaptic function. However, the exact function of these microglia in major depressive disorder (MDD) remains unclear. Here, we report that in a chronic unpredictable mild stress (CUMS) model of depression, the expression of Dkk3 protein, the dickkopf Wnt signaling pathway inhibitor 3, was downregulated in the cornu ammonis 1 (CA1) region of the hippocampus. Neuronal-specific knockdown of Dkk3 increased microglial activation and engulfment, thereby contributing to depressive- and anxiety-like behaviors, via the Wnt-CX3CL1/CX3CR1 signaling pathway. With the ablation of microglia or chemical inhibition of CA1 pyramidal neurons, depressive-like behaviors were abolished. Moreover, treatment with a CX3CL1 McAb or XAV-939, an inhibitor of the Wnt pathway, ameliorated CUMS-induced behavioral deficits and decreased microglial phagocytosis of neuronal spines. Taken together, these results demonstrate that Dkk3 plays a critical role in regulating microglial engulfment, an effect which induces long-lasting disruptions of CA1 neurons in response to stress. These findings reveal important new mechanistic insights into the potential for Dkk3 to exert a protective role against MDD pathogenesis.