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.