Autism spectrum disorder (ASD) is a neurodevelopmental and behavioral disorder characterized by social and communication deficits, restricted and repetitive behaviors, and fixated interests. The underlying causes of ASD remain unclear, and no pharmacological treatments are approved for its core symptoms. Our previous studies reported elevated nitric oxide (NO) levels, nitrosative stress, and S-nitrosylation (SNO) in the Shank3 KO autism mouse model. Notably, pharmacological inhibition of neuronal nitric oxide synthase (nNOS) reversed autism-like behaviors such as impaired sociability, anxiety, and repetitive behaviors as well as underlying molecular and synaptic abnormalities. However, the mechanism of NO-mediated pathology remains poorly understood. Therefore, in this study, we investigate thioredoxin (Trx), a key antioxidant that both regulates and is regulated by NO, and we aim to study its potential as a therapeutic target for autism. Beyond Trx’s antioxidant function, Trx modulates transcription factors involved in antioxidant gene expression, hypoxia response, apoptosis, and inflammation. Additionally, it denitrosylates S-nitrosylated proteins, protecting cells from nitrosative stress. We hypothesize that excessive NO in Shank3 KO mice increases S-nitrosylation of Trx1, leading to its inactivation and degradation. This may reduce antioxidant defenses and increase oxidative/nitrosative stress, contributing to synaptic dysfunctions associated with ASD. We observed reduced expression of Trx system components in addition to decreased Trx1 activity in the cortex of Shank3 KO mice and cells. Pharmacological inhibition of Trx1 with PX-12 further decreased Trx1 and Nrf2 levels, disrupted GABAergic and glutamatergic signaling, and impaired novelty-seeking and social behaviors. These findings underscore the critical role of the Trx1 system in redox balance and ASD-related phenotypes.

Supervisor: Prof. Haitham Amal