Scientists at Hebrew University of Jerusalem have identified a promising new mechanism behind autism-related behaviors, showing that blocking nitric oxide—a common signaling molecule in the brain—reverses autism-like traits in mice and protects human nerve cells from cellular dysfunction.
The research, published in Molecular Psychiatry, reveals an elegant chain of events: nitric oxide disables TSC2, a protective protein that normally acts as a brake pedal for cellular growth. When nitric oxide attaches to TSC2 through a process called S-nitrosylation, it marks the protein for destruction, allowing the mTOR pathway—which controls protein production in cells—to accelerate uncontrollably.
Shashank Kumar Ojha, a doctoral student who led the work, and Professor Haitham Amal studied genetically modified mice lacking either the Shank3 or Cntnap2 genes—both associated with autism in humans. The mice showed elevated nitric oxide attached to TSC2 proteins. When treated with a nitric oxide-blocking drug, the TSC2 brake protein remained intact and the mTOR pathway normalized.
The behavioral effects were striking. Mice that received the nitric oxide blocker showed improved social interaction and reduced anxiety compared to untreated mice with the same genetic mutations.
The team also found the same pattern in laboratory-grown human nerve cells carrying the Shank3 mutation. The nitric oxide blocker protected the brake protein and calmed the cellular overdrive in human cells just as it did in mice.
Perhaps most intriguingly, blood plasma samples from autistic children showed significantly lower TSC2 levels and signs of overactive mTOR compared to neurotypical controls.
Now, the essential caveats: this is a mouse study with a small sample of human participants. Nitric oxide interacts with multiple brain proteins beyond TSC2, and other chemical pathways certainly contribute to autism development. The path from these findings to clinical treatment is long and uncertain.
That said, the research does something valuable. As Professor Amal noted: "Autism is not one condition with one cause...by identifying a clearer chain of events...we hope to provide...a more precise map for future research."
