Think of the brain as a city with traffic lights that keep signals flowing smoothly. In a new study, researchers followed a clue about nitric oxide, a common chemical messenger, and found that, in some forms of autism, if it increases, it may act less like a helpful signal and more like a “stuck button.” When nitric oxide sets off this chain reaction, a key safeguard protein called TSC2 gets lost, and a major control system in cells, mTOR, which helps manage growth and protein-making, can surge into abnormal overdrive. The encouraging twist: when the researchers interrupted that specific step, the system calmed down, pointing to a more concrete “where to look” in the biology of autism and a possible direction for future therapies.
Nitric oxide is usually one of the brain’s quiet helpers: a tiny molecule that slips between cells, fine-tuning communication and keeping neural systems responsive. But new research from the Hebrew University of Jerusalem, led by Prof. Haitham Amal, The Satell Family Professor of Brain Sciences, suggests that in some forms of autism spectrum disorder (ASD), nitric oxide may also help set off a biochemical domino effect—one that pushes a key cellular control system into overdrive.
The study was first-authored by PhD student Shashank Ojha, published in Molecular Psychiatry, one of the top psychiatry journals and among Nature Publisher journals, explores a molecular pathway that connects three important players: nitric oxide, a protective protein called TSC2, and the mTOR pathway, a major regulator of how cells grow and produce proteins. Many researchers have suspected that mTOR signaling can become dysregulated in ASD. What has been harder to pin down is the “how”, the specific steps that might link risk factors to mTOR changes in the brain.
Prof. Amal’s team focused on a process called S-nitrosylation, a chemical modification that occurs when nitric oxide attaches to proteins and changes their behavior. Using a systems-level protein analysis approach, the researchers found that proteins involved in the mTOR pathway were especially affected, prompting them to investigate a critical checkpoint: TSC2, which normally acts like a brake on mTOR activity.
Their experiments indicated that nitric oxide can modify TSC2 in a way that marks it for removal. With less TSC2 available, the brake weakens and mTOR activity can rise. Because mTOR influences protein production and other essential cellular functions, this kind of overactivation may affect how neurons function and communicate.
To test whether this pathway could be interrupted, the team used pharmacological approaches that reduce nitric oxide production in neurons. When nitric oxide signaling was dampened, the researchers observed prevention of the TSC2 modification and a normalization of mTOR activity, along with improvements in measures linked to altered protein translation and autism-related outcomes in their experimental system.
In a complementary approach, the researchers engineered a version of TSC2 designed to resist nitric oxide-related modification. Preventing that single chemical “tag” helped protect TSC2 levels and reduced downstream effects tied to excessive mTOR signaling, supporting the idea that this specific modification may play a meaningful role in driving the pathway.
Importantly, the study also examined clinical samples from children with ASD, including children with SHANK3 mutations as well as idiopathic ASD (cases without a single known genetic cause) recruited by Dr. Adi Aran, MD. The researchers reported patterns consistent with the proposed mechanism, including reduced TSC2 levels and increased mTOR signaling activity, which adds real-world relevance to the molecular findings.
“Autism is not one condition with one cause, and we don’t expect one pathway to explain every case,” said Prof. Haitham Amal. “But by identifying a clearer chain of events, how nitric oxide-related changes can affect a key regulator like TSC2 and, in turn, mTOR, we hope to provide a more precise map for future research and, eventually, more targeted therapeutic ideas.”
This study further emphasizes the importance of developing nitric oxide inhibitors for ASD. Further, by outlining a specific nitric oxide–TSC2–mTOR connection, the study offers a fresh framework for understanding how cellular signaling can go off-balance in ASD and suggests new places scientists can look when developing and testing future interventions.
About Autism Spectrum Disorder (ASD)
ASD is a neurodevelopmental condition characterized by differences in social communication and behavior. It is highly diverse, with many genetic and biological factors contributing to risk and outcomes. Researchers increasingly study cellular pathways like mTOR because they influence how brain cells grow, adapt, and build connections.