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Endothelial SHANK3 Regulates Tight Junctions in the Neonatal Blood-Brain Barrier through β-Catenin Signaling

ABSTRACT: Autism spectrum disorder (ASD) is a neurodevelopmental condition caused by a combination of genetic and environmental factors. The blood-brain barrier (BBB) plays a key role in regulating environmental influences on the brain, yet its contributions to ASD remain unclear. We report that endothelium-specific SHANK3 (eSHANK3) is expressed in brain endothelial cells (BECs) that form the BBB. Our analysis of eSHANK3 interactions in BECs shows significant enrichment of proteins involved in membrane and cell junction functions. We found that eSHANK3 maintains tight junction (TJ) integrity, which is essential for BBB function. Loss of Shank3 disrupts TJs, increasing paracellular passage through the endothelium. In vivo, eShank3 knockout (KO) mice show BBB hyperpermeability, reduced neuronal excitability, and impaired ultrasonic communication. Although BBB permeability is restored in adulthood, the mutant mice continue to have reduced neuronal excitability and impaired sociability. Further analysis reveals that neonatal BBB hyperpermeability is due to β-Catenin imbalance caused by eShank3-KO. Restoring β-Catenin signaling rescues neuronal and social behavior deficits. These findings uncover a new pathogenic mechanism linked to Shank3 in ASD and suggest that neonatal BECs in the BBB could be a potential therapeutic target for ASD.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture, Endothelium

DISEASE(S): Autistic Disorder

SUBMITTER: Yongeun Kim

LAB HEAD: Il Hwan Kim

PROVIDER: PXD059466 | Pride | 2025-02-07

REPOSITORIES: pride

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			Action	DRS
	20201118_kim_c1.mzML	Mzml
	20201118_kim_c1.mzTab	Mztab
	20201118_kim_c1_1.raw	Raw
	20201118_kim_c1_2.raw	Raw
	20201118_kim_c1_3.raw	Raw

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