Regenerative
Mouse study links autism blood-vessel defect to a receptor that can be switched on
By Life and Health Today Staff, . Life and Health Today.
Researchers at The Ottawa Hospital and the University of Ottawa have identified a cellular defect in the blood vessels of the brain that, in a mouse model of autism, appears to drive behavioural symptoms, and have shown that switching on a single receptor can reverse those symptoms in adult animals.
The work, published in the journal Neuron, focused on mice carrying a deletion of a chromosomal region called 16p11.2, one of the more common genetic variants associated with autism spectrum disorder (ASD). Autism spectrum disorder is a neurodevelopmental condition, meaning it affects how the brain develops, with widely varying characteristics. No drug treatment currently exists for its behavioural symptoms.
The team, led by senior scientist Baptiste Lacoste of The Ottawa Hospital and the University of Ottawa, had previously shown that brain blood vessels do not function normally in these mice. The new work, headed by former doctoral student Julie Ouellette, traced the problem to endothelial cells: the cells that line the inside of blood vessels and regulate how quickly blood reaches active parts of the brain. That rapid, responsive blood supply is necessary for normal brain function.
According to Genetic Engineering News, which reported on the Neuron paper, the endothelial cells in the 16p11.2 deletion mice contained half the normal level of ATP, adenosine triphosphate, the molecule cells use to store and transfer energy. The researchers found that the deficit was specific to endothelial cells rather than spread across brain tissue generally, which they described as pointing to those cells as central to the disorder's biology in this model.
The consequence of low ATP, the team reported, was that the cells lacked adequate signalling through a surface protein called the P2Y2 receptor, a purinergic receptor, meaning one that responds to molecules in the purine family, which includes ATP. When the researchers activated P2Y2 using a pharmacological agent, endothelial cell function recovered, blood flow in the brain increased, and the behavioural symptoms seen in the adult mice, including hyperactivity, repetitive movements, and impaired motor learning, were reversed.
The drug used to activate P2Y2 in the experiments is already approved for human use in Japan and South Korea, where it is prescribed for dry eye syndrome. That approval is for a different condition and a different route of administration; it does not mean the drug is approved, or even being evaluated, for autism in any country.
Lacoste was quoted by Genetic Engineering News as saying: "It's as if these cells are asleep, and now we can wake them up. And we may only need to treat them once to wake them up permanently."
The study also noted that the experiments were conducted entirely in adult mice, meaning the researchers showed that the intervention could reverse symptoms that were already established, not just prevent them from forming. The team plans to test whether treating mice earlier in life produces additional benefit. A patent application has been filed for using P2Y2 activation in brain blood vessels to treat autism symptoms.
What this does not show is whether any of this applies to people. The 16p11.2 deletion mouse model reproduces one genetic variant associated with autism; it does not represent the full range of causes or presentations of the condition in humans. Mouse behaviour and human behaviour are measured differently, and a reversal of symptoms in a rodent model has frequently failed to translate into human benefit in neurodevelopmental research. The team has not announced a clinical trial, and Lacoste acknowledged in Genetic Engineering News that "the road from discovery to clinical trials is long."
The open question is whether the same endothelial ATP deficit exists in people with 16p11.2 deletions, and whether activating P2Y2 in human brain vasculature would be safe and achievable. Those questions would require human studies that have not yet been conducted. Anyone weighing what this finding means for themselves or someone they care for should discuss it with a clinician who knows the individual's history.