Indoleamine 2,3-dioxygenase inhibition attenuates lipopolysaccharide induced persistent microglial activation and depressive-like complications in fractalkine receptor (CX₃CR1)-deficient mice

An impaired ability to regulate the activation of microglia by fractalkine (CX₃CL1) leads to persistent neuroinflammation and behavioral alterations following lipopolysaccharide (LPS) challenge. While these responses are usually transient, LPS injection caused prolonged depressive-like behavior in fractalkine receptor deficient mice (CX₃CR1^-/-) that was associated with exaggerated microglial activation and induction of the tryptophan (TRP) degrading enzyme indoleamine 2,3-dioxygenase (IDO). IDO activation and subsequent generation of neuroactive kynurenine metabolites may have a pivotal role in the development of depression. Therefore, the purpose of this study was to determine the extent to which LPS-induced depressive-like behavior in CX₃CR1^-/- mice was dependent on IDO activation. CX₃CR1^-/- mice were implanted prior to LPS challenge with a slow release pellet of 1-methyl-tryptophan (1-MT), a competitive inhibitor of IDO. Here we show that the depressive-like behavior evident in CX₃CR1^-/- mice 72h after LPS injection was abrogated by inhibition of IDO. LPS also decreased body weight and locomotor activity in CX₃CR1^-/- mice, but these effects were independent of 1-MT. Consistent with the increased metabolism of TRP by IDO, the ratio of 3-hydroxykynurenine (3-HK) to TRP was increased in the brain 72h after LPS. Increased serotonin (5-HT) turnover was also evident in the brain. The LPS-associated increases in both 3-HK:TRP and 5-HIAA:5-HT ratios were prevented by the inhibition of IDO. Last, IDO blockade attenuated microglial activation in the prefrontal cortex and hippocampus 72h after LPS. Collectively these data indicate that LPS-induced IDO activation contributes to persistent microglial activation and depressive-like behavior in CX₃CR1^-/- mice.