Interactions between fractalkine (CX₃CL1) and fractalkine receptor (CX₃CR1) regulate microglial activation in the CNS. Recent findings indicate that age-associated impairments in CX₃CL1 and CX₃CR1 are directly associated with exaggerated microglial activation and an impaired recovery from sickness behavior after peripheral injection of lipopolysaccharide (LPS). Therefore, the purpose of this study was to determine the extent to which an acute LPS injection causes amplified and prolonged microglial activation and behavioral deficits in CX₃CR1-deficient mice (CX₃CR1^-/-).

CX₃CR1^-/- mice or control heterozygote mice (CX₃CR1^+/-) were injected with LPS (0.5 mg/kg i.p.) or saline and behavior (i.e., sickness and depression-like behavior), microglial activation, and markers of tryptophan metabolism were determined. All data were analyzed using Statistical Analysis Systems General Linear Model procedures and were subjected to one-, two-, or three-way ANOVA to determine significant main effects and interactions.

LPS injection caused a prolonged duration of social withdrawal in CX₃CR1^-/- mice compared to control mice. This extended social withdrawal was associated with enhanced mRNA expression of IL-1β, indolamine 2,3-dioxygenase (IDO) and kynurenine monooxygenase (KMO) in microglia 4 h after LPS. Moreover, elevated expression of IL-1β and CD14 was still detected in microglia of CX₃CR1^-/- mice 24 h after LPS. There was also increased turnover of tryptophan, serotonin, and dopamine in the brain 24 h after LPS, but these increases were independent of CX₃CR1 expression. When submitted to the tail suspension test 48 and 72 h after LPS, an increased duration of immobility was evident only in CX₃CR1^-/- mice. This depression-like behavior in CX₃CR1^-/- mice was associated with a persistent activated microglial phenotype in the hippocampus and prefrontal cortex.

Taken together, these data indicate that a deficiency of CX₃CR1 is permissive to protracted microglial activation and prolonged behavioral alterations in response to transient activation of the innate immune system.