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Restoring brain blood flow reversed autism-linked behaviours in adult mice
Researchers at The Ottawa Hospital reversed autism-linked behaviours in 16p11.2 mice by restoring blood flow in brain vessels that held half the normal ATP. The drug that did it is already approved for people in Japan and South Korea, though for dry eye, not autism.
The Scientist · Science desk
What happened
- The dysfunction starts in the endothelial cells lining the brain's smallest blood vessels, the capillaries, and not in the neurons those vessels feed.
- In the 16p11.2 mice, those vessels cannot open on demand to supply active neural circuits, because their P2Y2 receptor signalling is impaired.
- Switching the P2Y2 receptor back on reversed hyperactivity, repetitive movements and motor-learning deficits.
- The results were published on September 30 in the journal Neuron.
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Why it matters
- capability No approved drug targets the biology behind these autism symptoms, so a specific vascular receptor gives drug developers a defined target.
- precedent The team frames the compound's existing human approval as an accelerated route to trials, shorter than developing a molecule from scratch.
- constraint Because the behaviour was measured in one autism-linked variant in mice, the work does not show the vascular route matters for autism's other causes or in people.
For years, autism research concentrated on neurons and the synapses that wire them together [5]. Lacoste's lab had found something different in mice carrying the 16p11.2 deletion: their blood vessels fail to develop and work normally [10]. The earlier work did not show which way the effect ran. Sluggish vessels might be a byproduct of a differently built brain, or they might drive the behaviour themselves.
The explanation the team lands on runs through ATP. Inside a cell it is fuel; outside the cell, ATP is a signal that binds the P2Y2 receptor on the vessel wall and triggers dilation [11]. First author Julie Ouellette and colleagues gave the mice a compound built to bind and switch that receptor on [9]. It restored healthy calcium signalling inside the endothelial cells and brought responsive blood flow back across the brain [12].
The vessels' failure to respond first shows up during early development [13], the window when a brain is being built. The treatment worked in animals that were already fully grown [14]. That points to a deficit that can still be reversed after development is over.
How far this vascular explanation reaches is unsettled. The 16p11.2 microdeletion is one of the most common copy-number variants linked to autism [17], but it is one variant, and the behavioural work was done in mice.
"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 [18].
What to watch
- Whether a P2Y2 agonist produces any behavioural effect in a human trial, and in which autism populations.
- Whether the same vascular defect turns up in autism-linked variants other than 16p11.2.
- How such a compound would be delivered to the brain if it were tested for autism.