Researchers at The Ottawa Hospital and the University of Ottawa have reversed established behavioral symptoms in a mouse model of autism by activating a single receptor on brain endothelial cells — using a drug already approved for human use in Japan and South Korea for dry eye syndrome. The work, published in Neuron, identifies endothelial P2Y2 receptor activation as a candidate therapeutic strategy for the 16p11.2 deletion form of autism spectrum disorder (ASD).

The study, led by former PhD student Julie Ouellette, PhD, and senior author Baptiste Lacoste, PhD, builds on the team's earlier finding that cerebral blood vessels malfunction in 16p11.2 deletion mice. The 16p11.2 deletion is one of the most common genetic mutations found in autism. Lacoste's group was the first to examine what happens in the brain's vasculature in this model.

The new paper pins the mechanism down. Endothelial cells in the 16p11.2 deletion mice carry roughly half the normal level of intracellular ATP. "We demonstrate that 16p11.2 deletion induced EC dysfunction is caused by a bioenergetic failure with reduced intracellular ATP," the authors wrote. The energetic deficit was confined to endothelial cells, which the investigators argue positions these cells as key contributors to ASD pathophysiology rather than bystanders.

The functional consequence is measurable. Endothelial cells normally ensure that blood reaches active brain regions rapidly, a supply required for proper brain function. In the deletion mice, those cells respond too slowly. The deficit appears early in brain development and produces behavioral symptoms later in life, including hyperactivity, repetitive movements, and motor learning impairment.

Receptor activation restores function

ATP is not only an energy currency here — it also acts as a signaling molecule. The problem in the mutant cells, the team found, is the loss of signaling through P2Y2, a purinergic receptor on the cell surface. Restoring that signaling pharmacologically produced effects across three experimental settings.

"Activation of ATP signaling via endothelial P2-class purinergic receptors, specifically P2Y2, rescued EC dysfunction, restoring angiogenic capacity in vitro, endothelium-dependent cerebrovascular reactivity ex vivo, and activity-dependent cerebral blood flow (CBF) in vivo," the team stated. "A selective pharmacological P2Y2 agonist also rescued adult 16p11.2-deficient behavioral phenotypes."

The agonist used is already approved in humans in two markets for an unrelated indication, dry eye syndrome — a fact that could shorten any translational path, though the researchers themselves caution on timeline. "The road from discovery to clinical trials is long, but we're excited by the possibility that our findings might one day improve the daily lives of people with autism," said Lacoste, senior scientist at The Ottawa Hospital and professor at the University of Ottawa.

One observation stands out for therapeutic development. Treatment was delivered to adult mice, meaning the behavioral symptoms were already well established before intervention — and the reversal still worked. Lacoste offered a striking framing: "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. We will test that further, but it's an encouraging feature for a future treatment."

That durability claim remains untested, as Lacoste noted. The team's conclusion in print is more measured: "These findings suggest that P2Y2 receptor activation represents a promising strategy to rescue brain EC dysfunction and, in turn, improve autism-related behaviors in the 16p11.2 deletion ASD syndrome."

What the study does and does not show

The evidence base is a single genetic mouse model. The results link one specific ASD-associated mutation to endothelial bioenergetics, but autism is a heterogeneous condition, and the paper does not address whether the mechanism generalizes to other genetic forms or to idiopathic ASD. No human data are reported. The behavioral endpoints — hyperactivity, repetitive movements, motor learning — are mouse phenotypes, not clinical outcomes.

The next experiments are already defined. The team plans to treat mice earlier in life to test whether intervention before symptom onset offers additional benefit beyond the adult-mouse rescue already demonstrated. The group has also filed a patent application covering the use of P2Y2 activation in blood vessels to treat autism symptoms and is open to drug development partnerships aimed at eventual clinical trials.