130. Kynurenine 3-monooxygenase mediates inflammation-induced behavioral despair behavior in mice

Abstract

Patients suffering from chronic diseases are 5–10 times more likely to develop depression than the general population. Clinical data suggests that pro-inflammatory cytokines are important contributors to the pathogenesis of comorbid depression. Research into mechanisms potentially involved in this association have implicated the cytokine-inducible enzyme, indoleamine 2,3-dioxygenase (IDO). This is the rate limiting enzyme of the kynurenine pathway, and preclinical studies have demonstrated that IDO is critical for the development of inflammation-associated behavioral changes. Consistent with previous reports, we found that IDO expression is uniformly up-regulated in distinct brain regions, including amygdala, striatum, and hippocampus, following immune challenge. However, the expression profile of downstream kynurenine pathway enzymes was brain region-dependent. The metabolism of kynurenine by kynurenine 3-monooxygenase (KMO) yields neurotoxic metabolites, and previous work supports the hypothesis that an elevation in these metabolites during neuroinflammation precipitates the resultant depression behaviors. To test this hypothesis, lipopolysaccharide (LPS) was administered intraperitoneally to wild-type (WT), KMO heterozygous (KMO +/−) or KMO knockout (KMO −/−) mice. Depressive-like behaviors were measured 24 h after LPS or saline treatment. LPS induced a decrease in sucrose preference (anhedonia) and in open field central area duration (anxiety-like behavior) in all three genotypes. However, KMO +/− and KMO −/− mice were protected from LPS-induced increase in immobility during the tail suspension test indicating that neurotoxic kynurenine metabolism is an important mediator of behavioral despair.