Endothelial SHANK3 Controls Tight Junction of Neonatal Blood-Brain Barrier

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disability condition arising from the combination of genetic and environmental factors. Despite the blood-brain barrier (BBB) serving as a crucial gatekeeper, conveying environmental influences into the brain parenchyma, the contributions of BBB in ASD pathogenesis remain largely uncharted. Here we report that a novel form of SHANK3, a gene strongly associated with Phelan-McDermid syndrome and ASD2, expresses in the BBB-forming brain endothelial cells (BECs) and regulates tight junctional (TJ) integrity essential for maintaining the BBB’s barrier function. Loss of Shank3 disrupts the TJ of BECs, leading to increased paracellular passage through endothelial linings. Neonates with endothelium-specific SHANK3 knockout exhibit increased BBB permeability, reduced neuronal excitability, and impaired ultra-sonic communications. Surprisingly, while BBB permeability is restored during adult age, the mutant mice continue to display reduced neuronal excitability, impaired sociability, and repetitive responses. Further investigation reveals that the hyperpermeability resulting from TJ disruption is attributed to the β-Catenin imbalance triggered by SHANK3 knockout, which is rescued by normalizing β-Catenin signaling in vitro and in vivo. These findings highlight a previously unknown pathogenic mechanism stemming from the ASD-risk SHANK3, emphasizing the significance of neonatal BECs in the BBB as a potential therapeutic target of ASD