The role of the kynurenine pathway in the pathophysiology of autism-like phenotype induced by maternal inflammation in male mice.

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with core symptoms that may include deficits in communication, social challenges, and repetitive/stereotyped behavior. The etiology of ASD is not well defined, but both genetic and environmental risk factors have been identified. In animal models, prenatal maternal immune activation precipitates the development of a behavioral phenotype resembling ASD, but the mechanisms by which this occurs are not fully understood. Inflammation can upregulate the kynurenine pathway metabolism through the enzyme indoleamine 2,3-dioxygenase-1 (IDO). Increased levels of kynurenines during development can have deleterious consequences leading to behavioral deficits in adulthood. We sought to determine whether the kynurenine pathway plays a pathogenic role in the development of an ASD-like phenotype using a well-characterized mouse model of maternal immune activation (MIA). Multiparous IDO null (IDO-/-) or C57BL/6 J wild-type dams were administered the viral mimetic polynosinic:polycytidylic acid (Poly IC) at gestational day 12.5. A similar immune response to Poly IC occurred in the maternal plasma and placenta of both genotypes, while kynurenine metabolism was only increased in the fetal tissue of WT mice exposed to Poly IC challenge. Interestingly, N-methyl-d-aspartate (NMDA) receptor subunit expression was reduced in the fetal brains of male WT, but not IDO-/-, after MIA with Poly IC. Here, we used machine-learning as an advanced method to evaluate ultrasonic vocalizations. Offspring exposed to prenatal MIA exhibited fewer and less complex ultrasonic vocalizations along with diminished social preference; however, MIA-induced repetitive/stereotyped behaviors were only present in WT mice. Taken together, our data indicate that fetal IDO1-dependent kynurenine metabolism mediates distinct components of the MIA-induced ASD-like phenotype in male mice, which may be related to alterations in the expression of NMDAR subunits during neurodevelopment.