Increased oxidative stress in the cerebellum and peripheral immune cells leads to exaggerated autism-like repetitive behavior due to deficiency of antioxidant response in BTBR T + tf/J mice

Abstract

Autism is a neurodevelopmental disorder that affects social cognitive abilities resulting in communication or sensory deficits, and stereotyped behaviors in millions of people worldwide. Oxidant-antioxidant imbalance contributes significantly to the neurobehavioral dysregulations and severity of symptoms in patients with autism, however it has not been explored earlier whether it affects autism-like behavior directly. Therefore, we investigated oxidant-antioxidant balance in peripheral immune cells (neutrophils and CD3+ T cells) and cerebellum of BTBR T + tf/J (BTBR) mice which show autism-like behavior and the social C57BL/6 J (C57) mice. Further, we utilized buthionine sulfoximine (BSO), a glutathione depleting agent to assess the impact of oxidant-antioxidant dysregulation on autism-like behavior. Our study shows that BTBR mice have increased lipid/protein oxidation products in cerebellum and neutrophils/CD3+ T cells along with increased NADPH oxidase (NOX2) and inducible nitric oxide synthase (iNOS) expression. This was concurrent with lower levels of glutathione and enzymatic antioxidants such as superoxide dismutase (SOD) and glutathione peroxidase (GPx) in the cerebellum and peripheral immune cells. BSO administration led to further lowering of glutathione with a concurrent upregulation of iNOS, and NOX2 in cerebellum and peripheral immune cells. However, there was deficiency of an adaptive antioxidant response which was associated with exaggerated repetitive behaviors in BTBR mice. On the other hand, C57 mice also had increased oxidative stress after BSO treatment, however there was an enzymatic antioxidant response both in cerebellum and periphery. Overall, this study suggests that BTBR mice have increased oxidative stress with a deficient enzymatic antioxidant response that is associated with autism-like repetitive behaviors.