Cerebrovascular Alterations Associated with 16p11.2 Deletion Autism Syndrome

Abstract

Brain development and function are highly reliant on adequate establishment and maintenance of vascular networks. As such, early impairments in vascular health can lead to neurodevelopmental anomalies. Despite a wealth of knowledge on neuronal underpinnings of autism spectrum disorders (ASD), vascular contributions to ASD have remained largely overlooked. ASD are neurodevelopmental conditions associated with genetic origins such as the common 16p11.2 deletion, which leads to a haploinsufficiency of ~30 genes on chromosome 16 in humans and chromosome 7 in mice. We revealed 16p11.2 deletion-induced endothelial-dependent structural and functional vascular abnormalities in the mouse brain, establishing a novel link between cerebrovascular impairments and ASD. We demonstrated that endothelial cells (ECs) contribute cell-autonomously to 16p11.2-deficient phenotypes. Furthermore, we unmasked the molecular mechanisms involved in 16p11.2-deficient EC dysfunctions. We identified a reduced mitochondrial density with a bioenergetic failure, a lack of ATP availability, in 16p11.2-deficient ECs. Interestingly, in vitro ATP supplementation rescued 16p11.2-deficient EC dysfunctions. We discovered that this response was P2-class purinergic receptor dependent, particularly P2Y2 mediated. These findings underscore energy metabolism and purinergic receptors as vascular targets in ASD. Furthermore, we showed that Rock2 haploinsufficiency, a downstream effector of RhoA, improves 16p11.2-deficient endothelial network formation in vitro and ameliorates 16p11.2 deletion-associated adult mouse behaviors. Overall, this thesis revealed unsuspected cerebrovascular underpinnings in ASD as well as highlights the critical role of ECs in brain health. Taken together, this work provides insight into new players and mechanisms of ASD pathogenesis, which is a pre-requisite for the development of transformative therapeutics.