Aberrant regulation of IL-1 during pregnancy promotes the development of autism-related neurodevelopmental disorders in mice

Abstract

Abstract The etiologies of most neurodevelopmental disorders, including autism spectrum disorder (ASD), remain incompletely understood. Interestingly, recent epidemiological and experimental evidence suggests that hyperactive maternal immune activation (MIA) impedes normal brain maturation and can promote the development of autism-related phenotypes. Indeed, our studies and work by others demonstrate that offspring born to pregnant mice that were exposed to the innate immune activator PolyI:C develop many of the defining behavioral features of ASD, including defects in social preference, communicative impairments, and repetitive/stereotyped behaviors. Although increasing evidence implicates key roles for dysregulated gestational inflammatory responses in neurodevelopmental disorders, the specific immune pathways that provoke autism-related phenotypes remain poorly described. In our studies, we demonstrate that inhibition of IL-1 signaling during gestation provides significant protection against the development of social abnormalities, communicative deficits, and repetitive/stereotyped behaviors in the MIA model of neurodevelopmental disease. Moreover, we find that treatment of pregnant mice with bioactive IL-1beta is sufficient to induce the development of autistic-like behaviors in the subsequent offspring. Our findings identify key roles for IL-1 in neurodevelopmental disorders and suggest that IL-1 may serve as a biomarker to identify at-risk pregnancies.