Studies have suggested that heightened neuroinflammation contributes to the pathogenesis of depressive disorder. A major participant in neuroinflammation is microglia, and fractalkine signaling (which comprises the chemokine CX3CL1, mainly expressed by neurons, and its receptor CX3CR1, almost exclusively present on microglia in healthy brains) has been reported to critically regulate microglial activity. The aim of this study was to investigate whether CX3CR1 deficiency was associated with a different outcome following chronic unpredictable stress (CUS) and the possible mechanism. Wild-type (WT) and CX3CR1-deficient (CX3CR1-/-) mice were subjected to CUS for 3 weeks. CX3CR1-/- mice displayed a better performance through sucrose preference test, open field test and forced swim test, which demonstrated that CX3CR1 deficiency alleviated depressive-like disturbances, such as anhedonia, anxiety or hopelessness. Nevertheless, CX3CR1-/- mice also showed less severe cognitive impairment from the results of Morris Water Maze and Novel object recognition. Long-term potentiation was recorded to test the synaptic plasticity and its result was consistent with that of cognitive ability tests. Both results of real time-PCR and immunofluorescence staining demonstrated that CX3CR1 deficiency facilitated the alternative activation of microglia, thus attenuated the release of inflammatory cytokines, which was verified by ELISA and flow cytometry. Maybe due to the mitigated neuroinflammation, CX3CR1-deficient mice showed higher resilience to CUS-induced blood brain barrier hyperpermeability and loss of dendrite spine (as showed by Golgi and DiI staining) than WT group. All of above results indicated that hampering neuron-microglia communication via CX3CR1-CX3CL1 pathway attenuated the effects of CUS on depressive-like disturbances and cognitive impairment.
Keywords: CX3CR1(−/−); Chronic unpredictable stress; Dendrite spines; Microglia; Neuroinflammation.
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