- 16p11.2 deletion causes endothelial-cell selective bioenergetic failure characterised by reduced intracellular ATP in brain vasculature.
- ATP supplementation restores 16p11.2-deficient endothelial function via P2 purinergic receptor activation, specifically P2Y2.
- P2Y2 activation restored cerebrovascular reactivity, activity-dependent cerebral blood flow, and rescued ASD-associated behaviours in 16p11.2-deficient mice, indicating therapeutic potential.
Neuron. 2026 Sep 30:S0896-6273(26)00692-6. doi: 10.1016/j.neuron.2026.09.009. Online ahead of print.
ABSTRACT
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.
PMID:42815469 | DOI:10.1016/j.neuron.2026.09.009
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