CX3CR1 (fractalkine receptor)-deficient mice exhibit resilience to chronic unpredictable stress-induced depressive-like behavior and suppressed neurogenesis

We recently demonstrated that microglia undergo dynamic alterations in activation state during the development of chronic unpredictable stress (CUS)-induced depressive-like behavior in mice. Moreover, manipulations of microglial activation, which counteracted these dynamic alternations, reversed the depressive-like behavioral symptoms. Here, we sought to determine whether CX3CR1-deficient mice, which display a mildly activated microglial phenotype, show increased or decreased sensitivity to CUS-induced depressive-like behavior. Experiments were conducted on homozygous mice with microglia-specific transgenic expression of GFP under the CX3CR1 promoter, in which the CX3CR1 gene was functionally deleted, and their C57BL wild-type (WT) controls. We found that following five weeks of CUS exposure, microglia numbers were significantly reduced in the hippocampal dentate gyrus (DG), but not CA3 region, in both WT and CX3CR1-deficient mice. However, only CUS-exposed WT mice showed a significant reduction in microglia soma size compared to controls, indicating resistance of CX3CR1-deficient microglia to stress-induced morphological changes. In addition, only CUS-exposed WT mice showed reduced sucrose preference and impaired novel object recognition memory, suggesting that CX3CR1-deficient mice do not exhibit CUS-induced depressive-like behavior, and show superior memory functioning under stress. Finally, doublecortin immunostaining of the DG revealed that exposure to CUS decreased neurogenesis in WT but not in CX3CR1-deficient mice. We conclude that CX3CR1 deficiency, which is associated with a mildly activated microglial phenotype, confers resilience to CUS-induced microglial alterations, depressive-like behavior, a nd suppressed neurogenesis.