Researchers at The Ottawa Hospital and at the University of Ottawa have been able to reverse certain behavioral symptoms in a mouse model of autism by fixing a problem in the endothelial cells (ECs) of brain blood vessels. Building on studies in a 16p11.2 deletion mouse model of ASD that identified brain endothelial cell abnormalities, the team linked 16p11.2 deletion with reduced levels of ATP in endothelial cells. They found that activating P2Y2 receptors rescued the 16p11.2-deletion-associated mouse behaviors.

The results present a promising new treatment target for autism spectrum disorder (ASD) symptoms. “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 Baptiste Lacoste, PhD, senior scientist at The Ottawa Hospital and professor at the University of Ottawa.

Baptiste is senior author of the team’s published paper in Neuron (“Purinergic receptor activation rectifies autism-associated endothelial dysfunction”), in which they concluded “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.”

Autism is a neurodevelopmental condition with widely varying characteristics. Some of the behavioral symptoms can make life more challenging. While many people with autism have found ways to manage these symptoms, no drug treatment exists.

Lacoste’s team previously discovered that blood vessels in the brain don’t work properly in mouse models with a 16p11.2 deletion, one of the most common genetic mutations seen in autism. They were the first to look at what was happening in the blood vessels of the brain. “Recent evidence in a 16p11.2 deletion mouse model of autism spectrum disorder (ASD) revealed brain endothelial abnormalities postnatally, but the endothelial alterations eliciting these changes remain unknown,” they wrote.

Through their newly reported work the researchers have now found that the problem began in the endothelial cells lining the blood vessels. These cells make sure blood quickly gets to the parts of the brain that are active. This responsive blood supply is needed for proper brain function.

However, the endothelial cells in the 16p11.2 deletion mice don’t respond quickly enough. This happens early in brain development and causes behavioral symptoms later in life, including hyperactivity, repetitive movements, and motor learning impairment.

Headed by former PhD student, Julie Ouellette, PhD, the research team looked at what was wrong with these endothelial cells and whether it could be fixed. They discovered that the cells had half the normal level of ATP. “We demonstrate that 16p11.2 deletion induced EC dysfunction is caused by a bioenergetic failure with reduced intracellular ATP,” they explained. While ATP is usually considered an energy molecule, in this case the cell was missing its target, called a P2Y2 receptor, on its surface. “The identified energetic failure was restricted to ECs, emphasizing these cells as key contributors to ASD pathophysiology,” the investigators added.

By activating this P2Y2 receptor, the researchers were able to restore the cell’s function, increase blood flow in the brain, and reverse the behavioral symptoms in adult mice. This was achieved using a drug known to activate P2Y2 and which is currently approved for humans in Japan and South Korea to treat dry eye syndrome.

“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.”

Lacoste said, “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.”

In their paper the authors concluded, “Taken together, this study demonstrates that metabolic reprogramming of brain ECs via purinergic receptor engagement represents a promising therapeutic avenue for ASD.” They also point out that the study only looked at adult mice. This means targeting P2Y2 could reverse behavioral symptoms that were already well established.

Next, the team plans to treat mice earlier in life to see if early treatment has additional benefits. The team has also filed a patent application for using P2Y2 activation in the blood vessels to treat autism symptoms. They are interested in exploring drug development with the aim of eventual clinical trials.