Auts2 regulated autism-like behavior, glucose metabolism and oxidative stress in mice.

Researchers studied mice with a deleted autism-related gene (AUTS2) and found these mice showed autism-like behaviors such as poor social skills and repetitive grooming. The gene deletion also caused problems with how the brain uses sugar for energy and increased harmful stress in brain cells. This suggests that metabolism problems might contribute to autism symptoms and could be targets for new treatments.

This preclinical study investigated the role of the AUTS2 gene in autism-like behaviors using genetically modified mice with AUTS2 deletion in specific brain neurons (Emx1-expressing cells). The research found that mice lacking AUTS2 displayed autism-like behaviors including impaired social interactions and repetitive grooming. At the molecular level, AUTS2 deletion disrupted brain glucose metabolism, reduced glucose uptake, and inhibited the pentose phosphate pathway. The study also documented increased oxidative stress, elevated reactive oxygen species, and disrupted mitochondrial function.

These findings suggest AUTS2 plays a crucial role in metabolic pathways that may contribute to autism pathology, potentially opening avenues for metabolism-targeted therapeutic approaches.

Findings suggest metabolism-targeted therapies could be explored for autism treatment, particularly approaches addressing glucose metabolism and oxidative stress. However, human studies are needed to validate these preclinical findings before clinical applications can be considered.

Animal study findings may not directly translate to humans. Sample size not reported, limiting assessment of statistical power. Study focused on specific brain cell type (Emx1-expressing neurons), so effects may not represent whole-brain AUTS2 function.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by abnormal social behavior and communication. The autism susceptibility candidate 2 (AUTS2) gene has been associated with multiple neurological diseases, including ASD. Glucose metabolism plays an important role in social behaviors associated with ASD, but the potential role of AUTS2 in glucose metabolism has not been studied. Here, we generated Auts2; Emx1conditional knockout mice with Auts2 deletion specifically in Exm1-positive neurons in the brain (Auts2-cKO mice) to evaluate the effects of Auts2 knockdown on social behaviors and metabolic pathways.

Auts2-cKO mice exhibited ASD-like behaviors, including impaired social interactions and repetitive grooming behaviors. At the molecular level, we found that Auts2 knockdown reduced brain glucose uptake and inhibited the pentose phosphate pathway. Auts2 knockdown also resulted in signs of oxidative stress, and we documented increased levels of reactive oxygen species and malondialdehyde as well as decreased levels of antioxidant molecules, including glutathione and superoxide dismutases in Auts2-cKO mouse brains compared to controls. Finally, Auts2 knockdown significantly disrupted mitochondrial homeostasis and inhibited activity of the SIRT1-SIRT3 axis.

Taken together, our findings indicate that loss of AUTS2 expression in Emx1-expressing cells induces multiple changes in metabolic pathways that have been linked to the pathology of ASD. Further characterization of the role of AUTS2 in Emx1-expressing cells in regulating the metabolism of brain neurons may identify opportunities to treat ASD and AUTS2-deficiency disorders with metabolism-targeted therapies.