Il Hwan Kim, PhD, a researcher at the University of Tennessee Health Science Center, has witnessed firsthand the challenges and heartaches faced by parents raising children with autism spectrum disorder (ASD) in the United States.

Little is understood about the mechanisms underlying ASD, especially given its prevalence, affecting approximately one in every 36 children. While the exact causes of autism remain largely unknown, scientists have long suspected that both genetic and environmental factors play significant roles.

Kim is leading a team of researchers whose discoveries have unveiled a crucial mechanism of the blood-brain barrier (BBB) in ASD development. “The blood-brain barrier is often considered the brain's gatekeeper,” Kim explained. “This barrier is like a highly selective security checkpoint, deciding what substances get access to our brain.”

At the heart of their research is a gene called SHANK3, known for its involvement in brain development and function. Mutations in SHANK3 have been linked to ASD, but until now, its role in the BBB was uncharted territory.

The ground-breaking study revealed that SHANK3 is expressed in the endothelial cells of the BBB, the very cells responsible for forming the barrier itself. “When SHANK3 was selectively knocked out in these cells in neonatal mice, our team observed a curious phenomenon: the male mice showed increased permeability of the BBB, meaning the barrier was more ‘leaky’ than usual,” Kim said. “This led to reduced neuronal excitability and impaired communication behaviors, which are hallmark features of ASD.”

Although the BBB’s permeability normalized as the mice matured, the neuronal and social impairments persisted into adulthood. “This suggests that early disruptions in the BBB could have lasting effects on brain function, underscoring a critical window during brain development that could be targeted for therapeutic interventions,” Kim said.

The team also identified a potential mechanism involving the protein β-Catenin, which is crucial for maintaining the tight junctions in the BBB. By modulating β-Catenin signaling in the affected mice, the researchers were able to restore the BBB’s function and significantly improve the mice’s neuronal activity and social behaviors.

The project findings, which have been published in Nature Communications, opens a promising new avenue for treatment.

While this research is still in its early stages and primarily conducted in mice, the implications are profound. It highlights the importance of the BBB in brain health and its potential as a therapeutic target for neurological disorders.