Summary:
Researchers at The Ottawa Hospital and the University of Ottawa have reversed core behavioral features in a mouse model of autism by restoring healthy blood vessel function in the brain. The team found that endothelial cells in a common genetic model of autism have impaired purinergic signaling and low ATP levels, and that stimulating the P2Y2 receptor with an existing drug corrects these deficits and improves behavior.
Key Facts:
- The vascular mechanism: In mice carrying the 16p11.2 deletion, brain endothelial cells fail to deliver rapid, activity-dependent blood flow because intracellular ATP is reduced and P2Y2 purinergic signaling is impaired.
- Reversing established symptoms: Pharmacological activation of endothelial P2Y2 receptors restored microvascular responsiveness, increased cerebral blood flow during neural activity, and reversed behavioral symptoms—hyperactivity, repetitive behaviors, and motor learning deficits—even in fully mature adult mice.
- Repurposing potential: The compound used to activate P2Y2 is already approved for human use in Japan and South Korea for dry eye disease, which could accelerate translation toward clinical development for autism-associated symptoms.
Source: The Ottawa Hospital / University of Ottawa
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with diverse cognitive, sensory, and behavioral profiles. While many autistic people develop effective coping strategies, some experience persistent challenges such as impaired motor learning, disruptive hyperactivity, and compulsive repetitive behaviors. Currently, no targeted pharmacological treatments address these specific neurobiological mechanisms.
Most research on ASD has focused on neurons and synaptic wiring. Challenging that neuron-centric view, Dr. Baptiste Lacoste and colleagues investigated the role of the brain’s vasculature. Their earlier work showed that blood vessels do not develop or function normally in mouse models with the 16p11.2 microdeletion, a common copy number variation linked to human autism.
In a new study published September 30 in the journal Neuron, the team shows that correcting this vascular dysfunction can directly normalize brain physiology and reverse established behavioral deficits.
“The road from discovery to clinical trials is long, but we’re encouraged by the possibility that these findings could one day improve daily life for people with autism,” said Dr. Lacoste.
“Waking up” dormant endothelial cells
The dysfunction originates in brain endothelial cells—the single-cell layer lining cerebral capillaries. Under normal conditions, these cells rapidly dilate or constrict blood vessels to deliver oxygen and nutrients to regions of high neural activity, a process called neurovascular coupling. In mice with the 16p11.2 deletion, this rapid hemodynamic response is blunted during critical developmental windows, which contributes to later behavioral changes including hyperactivity, repetitive movements, and motor coordination problems.
First author Dr. Julie Ouellette and colleagues found that endothelial cells from 16p11.2-deficient mice contain about half the normal intracellular ATP. Beyond its role as cellular energy currency, ATP also acts extracellularly on purinergic receptors—specifically P2Y2 receptors on endothelial surfaces—to trigger vasodilation. With reduced ATP, purinergic signaling is insufficient and vessels remain sluggish.
To restore function, the researchers used a pharmacological agonist that stimulates the P2Y2 receptor. Treatment normalized calcium signaling in endothelial cells, repaired activity-dependent blood flow across the brain, and systematically reversed motor learning impairments, repetitive behaviors, and hyperactivity in the affected mice.
“It’s as if these cells are asleep, and now we can wake them up,” Dr. Lacoste said. “We may only need a single treatment to produce lasting improvement; we will test that further, but it’s an encouraging prospect for future therapy.”
Translational horizons and adult plasticity
A critical finding is that the intervention worked in fully adult mice, showing that autism-associated behavioral traits are not necessarily permanently hardwired and can be rescued after neural circuits mature. Because the P2Y2 agonist used is already approved for human use in some countries to treat dry eye disease by stimulating ocular mucosal blood flow and secretion, the path to clinical translation is more direct than for a novel drug.
The research team has filed a patent application for using P2Y2 activation in cerebral blood vessels to treat autism-related symptoms and plans to proceed with preclinical drug optimization and eventual human trials. Future studies will also explore whether early neonatal treatment can prevent neurovascular and cognitive deficits from developing in the first place.
Funding: Canadian Institutes of Health Research
Editorial notes:
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full by our staff.
- Additional context was added by our editorial team.
About this ASD and neurodevelopment research:
- Media contact: Amelia Buchanan
- Source institution: The Ottawa Hospital, University of Ottawa
- Image credit: Image credited to Neuroscience News
- Original research (open access): Neuron (Sept 30, 2026). Title: “Purinergic receptor activation rectifies autism-associated endothelial dysfunction.” Authors: Julie Ouellette et al.
- DOI: 10.1016/j.neuron.2026.09.009
Abstract
Purinergic receptor activation rectifies autism-associated endothelial dysfunction
Recent studies in a 16p11.2 deletion mouse model of autism spectrum disorder revealed postnatal brain endothelial abnormalities, but the cellular mechanisms remained unclear. Using both juvenile (14-day-old) and adult male mice with the 16p11.2 deletion and wild-type controls, this work shows that the deletion produces a selective bioenergetic failure in brain endothelial cells, marked by reduced intracellular ATP. Supplementing ATP intra- or extracellularly restored endothelial function in vitro through activation of P2 purinergic receptors, notably P2Y2. Pharmacological activation of P2Y2 receptors reinstated cerebrovascular reactivity ex vivo, recovered activity-dependent cerebral blood flow in vivo, and rescued behavior deficits associated with the 16p11.2 deletion. Together, these results indicate that metabolic reprogramming of brain endothelial cells through purinergic receptor engagement is a promising therapeutic approach for ASD-related symptoms.