Pathogenic role for the kynurenine pathway in maternal immune activation-induced autism-like behavior in mice

Abstract

Prenatal inflammation is a risk factor for neurodevelopmental disorders. In rodent models, maternal immune activation (MIA) causes phenotypes in offspring that resemble many of the features of these human disorders, but the pathogenic mechanisms remain unclear. Immune activation upregulates the tryptophan metabolizing enzyme indoleamine 2,3-dioxygenase (IDO) which mediates many of the behavioral consequences of inflammation in adults, and experimentally increasing kynurenine levels of pregnant dams causes developmental consequences in the offspring. Therefore, we hypothesized that MIA-induced upregulation of IDO during gestation is a pathogenic mechanism by which fetal neurodevelopment is disrupted and autism-like phenotypes develop. Pregnant female IDO-/- mice or control C57BL/6J mice were administered 20 kg/mg polyinosinic:polycytidylic acid (poly I:C) or saline i.p. on gestational day 12.5. At various ages, autism-like behaviors were measured. Repetitive self-grooming behavior was significantly increased in WT-MIA male offspring compared to WT-saline controls. Self- grooming behavior in IDO-/- mice was not affected by MIA. MIA reduced preference for social novelty, measured in the 3-chamber test, in male offspring independent of IDO, while it increased social novelty preference in WT female mice. In mice with targeted deletion of kynurenine monooxygensase (KMO), endogenous kynurenine levels are markedly increased, and offspring of KMO KO dams exhibit several autism-like behaviors. Our data suggest that IDO may play an important pathogenic role in the development of specific autism-like behaviors caused by MIA.