The interplay between oxidative stress and inflammation supports autistic-related behaviors in 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 inflammation may contribute to ASD. Here we used RT-qPCR, RNA sequencing, immunohistochemistry, and flow cytometry to show that pro-inflammatory molecules were increased in the cerebellum and periphery of mice lacking Cntnap2 (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 and inflammation as well as motor and social impairments in Cntnap2-/- mice. This was accompanied by improved function of microglia cells in NAC-treated mutant animals. Intriguingly, social deficits, cerebellar inflammation and microglia dysfunction were induced by NAC in Cntnap2+/+ animals. Our findings therefore suggest that the interplay between oxidative stress and inflammation may support ASD-related behaviors in mice.

N-acetylcysteine counteracts immune dysfunction and autistic-related behaviors in theShank3bmouse model of Autism Spectrum Disorders

“…These results were accompanied by decreased levels of pro-inflammatory molecules in the cerebellum, as all molecules related to inflammation were reduced in both Shank3b +/- and Shank3b -/- mice. Similarly to our previous observations in the Cntnap2 model (12), an overall increase in the expression of pro-inflammatory molecules was observed in Shank3b +/+ mice treated with NAC; this might be caused by “antioxidative stress”, a stressful condition supported by the excessive elimination of oxygen radicals (39,40). It is however worth noting that despite this pro-inflammatory activity of NAC, we did not observe social impairment in the NAC-treated Shank3b +/+ group.…”

“…Several recent studies have described increased levels of pro-inflammatory molecules and oxidative stress in children with ASD and mouse models (7)(8)(9)(10)(11)(12)(13)(14)(15)(16). As recently proposed, inflammation may impair the maturation of vulnerable neurons, therefore supporting the onset of ASD (25).…”

“…In our previous work on mice lacking the ASD-relevant gene Cntnap2 , we showed that N-acetylcysteine (NAC) may act as anti-inflammatory molecule within the cerebellum and in the periphery (12). To assess whether ASD-related behaviors may be improved in the Shank3b model, NAC was intraperitoneally injected once a day for 28 days into Shank3b +/+ , Shank3b +/- , and Shank3b -/- mice.…”

“…We therefore administered the antioxidant/anti-inflammatory molecule NAC, which in our previous study was shown to target cerebellar as well as systemic inflammation in Cntnap2 -/mice (12). Differently from Cntnap2 -/mice, no rescuing effects were observed on motor deficits in Shank3b -/animals as detected by the open field and rotarod tests.…”

“…Shank3b -/- , Shank3b +/- , Shank3b +/+ mice were injected intraperitoneally with 50mg/kg NAC (Sigma-Aldrich) resuspended in PBS or vehicle (PBS) for 28 consecutive days as previously done (12).…”