The cellular and developmental basis of autism spectrum disorder (ASD) still represents a significant gap in our knowledge of this developmental disorder. To understand how ASD affects brain development, comprehensive disease models are needed. Such models will yield insight into the developmental programs that are affected in ASD and how these perturbations ultimately affect behavioral output.
It was well-known that inactivation of the E3 ubiquitin ligase UBE3A causes Angelman syndrome, whereas excess activity through duplication or triplication of the gene-encoding UBE3A is strongly linked to ASD. In previous work, Jason Yi and his colleagues utilized genetic information to understand how UBE3A activity is regulated in the cell1. By functionally testing various disease-linked missense mutations in UBE3A, Yi and colleagues found that UBE3A activity is regulated by phosphorylation at a single site. Phosphorylation dampens UBE3A activity, and blocking phosphorylation perturbs synaptic connectivity in mice. This phosphorylation site is mutated in ASD, suggesting that unregulated UBE3A activity increases the risk for this disorder.
To identify the brain developmental programs perturbed by UBE3A hyperactivation, Yi and his team at Washington University are investigating a mouse model harboring the ASD-linked mutation in UBE3A. His team is assessing how this mutation affects distinct populations of neurons at the onset of synaptogenesis, and how these early developmental events contribute to behavioral deficits in mature animals. The results of this study will further our understanding of the neuronal and developmental underpinnings of ASD.