Poster abstracts

Poster number 77 submitted by Diana Norden

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

Diana M. Norden (Department of Neuroscience, The Ohio State University ), Angela W. Corona, John Skendelas, Yan Huang (Department of Neuroscience, The Ohio State University ), Jason C. OConnor (Department of Pharmacology, University of Texas Health Science Center), Marcus Lawson, Robert Dantzer, Keith W. Kelley (Department of Animal Science, University of Illinois), Jonathan P. Godbout (Department of Neuroscience, Institute for Behavioral Medicine Research, The Ohio State University)

Abstract:
An impaired ability to regulate the activation of microglia by fractalkine (CX3CL1) leads to persistent neuroinflammation and the development of 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 amplified induction of several inflammatory mediators and the tryptophan (TRP) degrading enzyme indoleamine 2,3-dioxygenase (IDO). IDO activation and subsequent 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. To address this objective, 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 72 h after LPS injection was abrogated by
inhibition of IDO. In addition, LPS caused a time-dependent reduction in body weight and locomotor activity in CX3CR1-/- mice, but these reductions were independent of 1-MT. Consistent with increased metabolism of tryptophan by IDO, the ratio of 3-hydroxy-kynurenine (3-HK) to TRP was increased in the brain 72 h after LPS. Increased serotonin (5-HT) turnover was also evident in the brain at this time point. 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 the persistent activated morphology of microglia (i.e., Iba-1 immunoreactivity) in the prefrontal cortex and hippocampus 72 h after LPS. Collectively these data indicate that LPS-induced IDO activation contributes to persistent microglial activation and depressive-like behavior in CX3CR1-/- mice.

Keywords: Microglia, Depression, Indoleamine 2,3-dioxygenase