Mar 09, 2026
3 min read
Researchers have seen a direct link between normal brain oxygen and hyperactive cell growth often seen in autism.Protection of a specific protein from this normal gas behavior in animal models and human cell culture.
A newly discovered biological chain reaction explains how high levels of a common brain chemical can lead to cell proliferation in autism spectrum disorders.By seeing how nitric oxide inhibits a protective protein to accelerate cell growth, researchers have identified a specific target that could one day yield new drugs.The latest results were published in the journal Molecular Psychiatry.
Autism spectrum disorders involve differences in brain development that affect social communication and general behavior.The biology of these mutations involves many genetic and environmental factorsResearchers have noticed that a signaling pathway called mTOR often functions abnormally quickly in the brains of autistic individuals.
The mTOR pathway acts as a central regulator of cell growth, protein production, and energy utilization.When it's working properly, it helps brain cells make the connections necessary for learning and memory.The precise steps linking autism risk factors to this exponential developmental pathway remain a mystery.
A group of scientists suspected that nitric oxide might be the missing link.Nitric oxide is a simple gas that helps communicate with brain cells and regulate blood flow.People with autism have high levels of nitric oxide in their brains and blood.
When nitric oxide levels get too high, the gas can bind directly to various proteins and change how they function.This process of chemical labeling is called S-nitrosylation.The research team wanted to see if this particular chemical tag was responsible for pushing the cell's growth pathways into overdrive.
The study was led by Shashank Kumar Ojha, a graduate student, and Haitam Amal, a professor of brain science.All researchers are based at the Hebrew University of Jerusalem.They designed a series of experiments to determine exactly how nitric oxide interacts with proteins that control cell growth.
The research team began by looking at two types of laboratory mice.These mice were mutated to lack the Shank3 or Cntnap2 genes.Both mutations are associated with autism in humans and cause mice to show similar behaviors.
Using a special chemical tracer, Ojha and his colleagues looked at proteins in the mice's brains.They focused on a specific protein called TSC2.In healthy cells, TSC2 acts as a brake pedal for the mTOR growth pathway.
The researchers found that the mutant mice had abnormally large amounts of nitric oxide bound to their TSC2 proteins.This nitric oxide tag acted as a signal that identified the brake protein for the cell recycling center.This caused the cells to destroy their own TSC2 proteins.
Without the TSC2 brake pedal, the mTOR growth pathway spiraled out of control.This strain caused brain cells to produce proteins at an abnormal rate.This altered protein production disrupted normal brain cell function in both excitatory and inhibitory neurons.
To confirm this chain of events, scientists treated genetically engineered mice with a drug that prevents the brain from producing nitric oxide.The results showed a clear mechanistic connection.Blocking nitric oxide prevents the destruction of the TSC2 brake protein.
With the brake protein intact, the cell growth process slows down to normal speed.Brain cells stop producing excess proteins.The treatment successfully restores the natural balance of the cellular environment.
Oha and his team then conducted the reverse experiment using normal mice without any genetic mutations.They gave these healthy mice a chemical that artificially activated the mTOR growth pathway.These mice soon began to display behavioral traits associated with autism.
The researchers placed mice in a three-chambered box to test their sociability.Healthy mice treated with the pathway activator lost interest in interacting with unfamiliar mice.They preferred to spend time alone in an empty chamber.
The researchers also tested the mice in an elevated maze to measure anxiety levels.The mice with the activated growth pathway avoided the open areas of the maze.This behavioral change confirmed that an overactive growth path alone can lead to social deficits and anxiety.
The researchers also wanted to demonstrate that a specific nitric oxide binding site on the TSC2 protein was at the root of the problem.Using genetic engineering, they changed the brake protein in a way that prevented nitric oxide from binding to it.They then injected this modified protein into the prefrontal cortex of the mutant mice.
This small genetic modification successfully protects the brake protein from being destroyed by nitric oxide.As a result, the growth path of the cells returns to normal.The mice also became more social and spent more time exploring the open arms of the long maze.
To expand their research beyond animal models, scientists have grown human neurons in the laboratory.They engineered these human cells to carry the Shank3 gene mutation.Like the mouse model, these human cells showed loss of the brake protein TSC2 and an aggressive growth pathway.
Treatment of these human neurons with nitric oxide inhibitors produced familiar resultsThe drug protected the fried protein and calmed the tumor cellsThis confirmed that nitric oxide works similarly in human tissues
Finally, the researchers expected the same pattern in real patients.They analyzed blood plasma from autistic children together with samples from neurotypical children.Some autistic children had Shank3 genetic mutations, while others had autism without a genetic cause.
The human blood test mirrored the laboratory tests completely.Samples from autistic children contain very low levels of the TSC2 protein inhibitor.Their blood also showed clear signs of an overactive mTOR growth factor.
Although these experiments provide a clear picture of cell failure, the researchers note some limitations.The human blood samples came from a relatively small group of participants.Future studies will need to include much larger groups of people if this model holds for different types of autism.
In addition, nitric oxide interacts with many different proteins in the body, not just the TSC2 brake protein.Researchers agree that other chemical pathways may play a role in the biological development of autism.He plans to investigate these potential connections in future projects.
However, the discovery that blocking nitric oxide can restore normal cell function provides a clear target for drug development.Scientists can now focus on designing drugs that protect the TSC2 protein or safely reduce nitric oxide levels in the brain.This may eventually lead to interventions for people with specific genetic mutations.
As Amal explained in a press release about the study, "Autism is not a condition with one cause, and we do not expect one pathway to explain all cases. However, if we can identify a clearer sequence of events, how changes associated with nitric oxide affect key regulators such as TSC2 and, by extension, mTOR, we hope to provide a more precise map for future and ultimately treatment-oriented ideas."
Shashin Kumar Ojha, Maryam Kartavi, Vijaya Hammoudi, Manish Kumar Tripathi, and Heathman are authors of the study, "Nitric oxide-induced S-nitrosylation of TSC2 causes Shank3 and Cntnap2 dysregulation of mTOR in autism spectrum disorder models."
