Scientists Identify Brain Signal That May Trigger Autism's Domino Effect

A new study suggests that a tiny signaling molecule in the brain may trigger a biological chain reaction that contributes to autism spectrum disorder (ASD). The research, led by scientists at the Hebrew University of Jerusalem, was published in the journal Molecular Psychiatry and provides new insights into how cellular signaling may become unbalanced in some forms of autism.

The study focused on Nitric Oxide, a small molecule that normally acts as a messenger helping brain cells communicate with each other. Under typical conditions, nitric oxide helps regulate neural circuits and maintain healthy brain function. However, researchers found that in certain cases of ASD, rising levels of nitric oxide may trigger a harmful biochemical process that disrupts normal cellular control.

The team, led by neuroscientist Haitham Amal, investigated how nitric oxide interacts with TSC2, a protein that normally acts as a protective “brake” for an important cellular system known as the mTOR Pathway. This pathway regulates essential processes such as cell growth, metabolism, and protein production.

Researchers discovered that nitric oxide can chemically modify TSC2 through a process called S-nitrosylation, marking the protein for removal from the cell. When TSC2 levels decrease, its braking effect weakens, allowing mTOR activity to increase beyond normal levels. Excessive activation of this pathway may disrupt normal brain cell function and communication.

Importantly, the scientists found that blocking nitric oxide production prevented the modification of TSC2 and restored mTOR activity to healthier levels. Similar molecular patterns were also observed in samples from children with autism, including those with **SHANK3 mutations.

Although autism has many possible causes, the researchers believe this newly identified nitric oxide–TSC2–mTOR signaling pathway offers a clearer map for future studies. The findings may also help guide the development of targeted treatments aimed at restoring balanced cellular signaling in the brain.

REFERENCE: Shashank Kumar Ojha, Maryam Kartawy, Wajeha Hamoudi, Manish Kumar Tripathi, Adi Aran, Haitham Amal. Nitric Oxide-Mediated S-Nitrosylation of TSC2 Drives mTOR dysregulation across Shank3 and Cntnap2 Models of Autism Spectrum Disorder. Molecular Psychiatry, 2026; DOI: 10.1038/s41380-026-03514-6