Summary:
Researchers at The Ottawa Hospital and the University of Ottawa have successfully reversed core behavioral symptoms in a mouse model of autism by restoring healthy blood vessel function in the brain. The team discovered that endothelial cells in a common genetic model of autism suffer from purinergic signaling deficits, which can be corrected using an existing therapeutic drug that activates the P2Y2 receptor.
Key Facts:
- The Vascular Mechanism: Brain endothelial cells in mice carrying the 16p11.2 deletion fail to deliver rapid, responsive blood flow to active neural circuits due to depleted ATP levels and impaired P2Y2 purinergic receptor signaling.
- Reversing Established Symptoms: Pharmacologically activating the endothelial P2Y2 receptor restored microvascular function, boosted cerebral blood flow, and reversed established behaviors, including hyperactivity, repetitive movements, and motor learning impairments, even in fully mature adult mice.
- Repurposing Potential: The intervention utilized a P2Y2-activating compound already approved for human clinical use in Japan and South Korea for dry eye disease, opening an accelerated path toward translational development.
Source: The Ottawa Hospital / University of Ottawa
Autism spectrum disorder is a complex neurodevelopmental condition characterized by diverse cognitive, sensory, and behavioral phenotypes. While many autistic individuals thrive and develop coping mechanisms, certain associated symptoms, such as severe motor learning deficits, disruptive hyperactivity, and compulsive repetitive behaviors, can present significant daily challenges. To date, no targeted pharmacological therapies exist to address these underlying neurobiological mechanisms.
Traditionally, neuroscientists exploring autism have concentrated almost entirely on neurons and synaptic wiring. However, an innovative line of inquiry led by Dr. Baptiste Lacoste, senior scientist at The Ottawa Hospital and professor at the University of Ottawa, has challenged this neuro-centric dogma by examining the cerebral vasculature.
In previous work, Dr. Lacoste’s laboratory revealed that blood vessels fail to develop and function normally in mouse models carrying the 16p11.2 microdeletion, one of the most prevalent copy number variations associated with human autism.
Now, in a landmark study published September 30 in the journal Neuron, the team demonstrates that repairing this vascular defect can directly normalize neurological function and reverse established behavioral 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 Dr. Lacoste.
“Waking Up” Dormant Endothelial Cells
The root of the dysfunction lies in brain endothelial cells, the specialized single-cell layer that lines the inner lumen of cerebral capillaries. Under normal physiological conditions, endothelial cells rapidly dilate or constrict vessels to shuttle oxygen- and nutrient-rich blood to areas of high neural activity, a process known as neurovascular coupling.
In mice harboring the 16p11.2 deletion, this hemodynamic responsiveness falters during early developmental windows, blunting dynamic blood delivery and contributing to downstream behavioral changes later in life, including hyperactivity, stereotypic repetitive actions, and impaired motor coordination.
Investigating the molecular machinery driving this endothelial failure, first author Dr. Julie Ouellette and colleagues discovered that the vascular cells possessed only half the normal physiological levels of adenosine triphosphate (ATP). While ATP is best known as an intracellular energy currency, it also functions as a vital extracellular signaling molecule that binds to the purinergic P2Y2 receptor on endothelial surfaces to trigger vasodilation.
Without adequate purinergic receptor stimulation, the vessels remained sluggish and unresponsive.
To rescue the pathway, the researchers administered a pharmacological agonist designed to bind and stimulate the P2Y2 receptor. The treatment reestablished healthy calcium dynamics, repaired responsive blood flow throughout the brain, and systematically reversed motor learning deficits, repetitive behaviors, and hyperactivity.
“It’s as if these cells are asleep, and now we can wake them up,” said Dr. Lacoste. “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.”
Translational Horizons and Adult Plasticity
Crucially, the study was conducted in fully adult mice, demonstrating that autism-associated behavioral phenotypes are not permanently hardwired into neural architecture and can be rescued even after circuits have matured.
Because the team utilized a P2Y2 receptor agonist that is already approved for human application in Japan and South Korea (where it is prescribed to treat dry eye disease by stimulating ocular mucosal blood flow and secretion), the translational roadmap is significantly streamlined.
The researchers have filed a patent application for using P2Y2 activation in cerebral blood vessels to treat autism-associated symptoms, with plans to advance into preclinical drug optimization and eventual human clinical trials. Future work will also investigate whether administering the therapeutic during early neonatal development can prevent the onset of neurovascular and cognitive deficits altogether.
Funding: Canadian Institutes of Health Research
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this ASD and neurodevelopment Research:
- Media Contact: Amelia Buchanan
- Source: The Ottawa Hospital
- Image Credit: Image credited to Neuroscience News
- Original Research is Open Access: Neuron (Sept 30, 2026). “Purinergic receptor activation rectifies autism-associated endothelial dysfunction.” Authors: Julie Ouellette, Sareen Warsi, Phinea Romero, Purva Khare, Shama Naz, Leya Aubert-Tandon, Moises Freitas-Andrade, Chantal Pileggi, Sozerko Yandiev, Joanna Raman-Nair, James Yee, Nicole Blakeley, Balaji Govindaswamy, Cesar Henrique Comin, Mary-Ellen Harper, Devika Soundara Manickam, Fabrice Dabertrand, Armen Saghatelyan, and Baptiste Lacoste.
- DOI: 10.1016/j.neuron.2026.09.009
Abstract
Purinergic receptor activation rectifies autism-associated endothelial dysfunction
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 remained unknown.
Using 14-day-old and adult 16p11.2-deficient and wild-type male mice, we now show that the 16p11.2 deletion causes a bioenergetic failure selectively in endothelial cells (ECs) with reduced intracellular ATP levels. Intra- or extracellular ATP supplementation rescued the function of 16p11.2-deficient ECs in vitro via P2 purinergic receptor activation, specifically P2Y2 receptors.
Activating P2Y2 receptors restored cerebrovascular reactivity in 16p11.2-deficient arterioles ex vivo, activity-dependent cerebral blood flow in vivo, and rescued 16p11.2 deletion-associated mouse behaviors.
Taken together, this study demonstrates that metabolic reprogramming of brain ECs via purinergic receptor engagement represents a promising therapeutic avenue for ASD.
