Targeted Deletion of Kynurenine 3-Monooxygenase in Mice

Abstract

Background: Kynurenine 3-monooxygenase (KMO) is hypothesized to play a pivotal role in regulating tryptophan metabolism in health and disease. Results: Mice that were generated lacking KMO have alterations in the levels of several tryptophan metabolites. Conclusion: KMO is a critical regulator of tryptophan metabolism. Significance: KMO knock-out mice will be a useful research tool to dissect the biological and pathophysiological roles of tryptophan metabolism.

Adaptive and Behavioral Changes in Kynurenine 3-Monooxygenase Knockout Mice: Relevance to Psychotic Disorders

“…In line with our previous, more detailed biochemical assessment of mice from the same colony (19), KMO activity was essentially eliminated in adult Kmo −/− animals, though some enzyme activity (<3% of wild-type) was measurable in 2/10 knockout mice, possibly due to very minor oxidative conversion of kynurenine to 3-HK. Thus, while the present study does not categorically rule out the existence of functional KMO isoforms and non-enzymatic production of 3-HK, the present results confirm that a single KMO accounts almost exclusively for the formation of 3-HK from kynurenine in mice.…”

“…Thus, while the present study does not categorically rule out the existence of functional KMO isoforms and non-enzymatic production of 3-HK, the present results confirm that a single KMO accounts almost exclusively for the formation of 3-HK from kynurenine in mice. Because of its conceptual importance in the context of the present study, we also verified that the abolition of KMO was associated with a large reduction in cortical 3-HK levels and a substantial increase in cortical KYNA levels (19) but did not measure anthranilic acid levels, which are also significantly elevated in both periphery and brain of Kmo −/− animals (19) as well as in the serum of individuals with SZ (46). Unfortunately, we were not able to determine the brain levels of the KP metabolites 3-hydroxyanthranilic acid or cinnabarinic acid, which may play a role in the pathophysiology of SZ (47, 48), due to limits in assay sensitivity.…”

“…Thus, as demonstrated both after pharmacological KMO inhibition (16–18) and in mice with a genomic elimination of the Kmo gene (19), reduced KMO activity induces a shift in KP metabolism towards the pathway branch that produces KYNA (Supplemental Figure 1). Notably, after being released into the extracellular compartment, newly produced KYNA can act as an endogenous antagonist at ɑ7 nicotinic acetylcholine (ɑ7nACh)(20) and N-methyl-D-aspartate (NMDA) receptors (21–23), both of which are critically involved in brain development (24) and cognition (25).…”

“…Adult male Kmo −/− mice and Kmo +/+ (wild-type) were bred on C57/BL6 or FVB/N backgrounds, as previously described (19) and detailed in Supplemental Materials.…”

“…The present study was designed to investigate possible changes in gene expression in the brain of mice with a targeted deletion of Kmo ( Kmo −/− mice), to assess cerebral and cerebellar variations in KYNA levels in these mice (19), and to characterize the mutant animals behaviorally. Compared to Kmo +/+ (wild-type) animals, Kmo −/− mice exhibited differential expression of several SZ- and psychosis-related genes and also showed significant impairments in cognition, social interaction, anxiety-like behaviors and D-amphetamine-induced locomotor activity.…”