The interplay between oxidative stress and inflammation supports autistic-related behaviors in Cntnap2 knockout mice.

Abstract

Autism Spectrum Disorder (ASD) is a highly prevalent neurodevelopmental condition characterized by social communication deficits and repetitive/restricted behaviors. Several studies showed that oxidative stress and inflammation may contribute to ASD. Indeed, increased levels of oxygen radicals and pro-inflammatory molecules were described in the brain and peripheral blood of persons with ASD and mouse models. Despite this, a potential direct connection between oxidative stress and inflammation within specific brain areas and ASD-related behaviors has not been investigated in detail yet. Here, we used RT-qPCR, RNA sequencing, metabolomics, immunohistochemistry, and flow cytometry to show that pro-inflammatory molecules were increased in the cerebellum and periphery of mice lacking Cntnap2, a robust model of ASD. In parallel, oxidative stress was present in the cerebellum of mutant animals. Systemic treatment with N-acetyl-cysteine (NAC) rescued cerebellar oxidative stress, inflammation, as well as motor and social impairments in Cntnap2mice, concomitant with enhanced function of microglia cells in NAC-treated mutants. Intriguingly, social deficits, cerebellar inflammation, and microglia dysfunction were induced by NAC in Cntnap2animals. Our findings suggest that the interplay between oxidative stress and inflammation accompanied by genetic vulnerability may underlie ASD-related behaviors in Cntnap2 mutant mice.