Delayed loss of UBE3A reduces the expression of Angelman syndrome-associated phenotypes.

Background: Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by mutations affecting gene expression. Previous studies in mice revealed distinct critical periods during neurodevelopment in which reactivation of gene expression can prevent the onset of behavioral deficits. Whether UBE3A is required for brain function throughout life is unknown. Here, we address the importance of maintaining UBE3A expression after normal brain development.

Findings: Using a conditional mouse, we deleted the gene at three ages spanning brain maturation. We assessed the consequences of gene deletion by testing the mice in behavioral tasks previously shown to produce robust phenotypes in AS model mice. Early embryonic deletion of recapitulated all behavioral deficits of AS mice. In contrast, gene deletion at 3 or 12 weeks of age did not have a significant effect on most behavioral tasks and did not increase seizure sensitivity.

Conclusions: Taken together, these results emphasize that UBE3A critically impacts early brain development, but plays a more limited role in adulthood. Our findings provide important considerations for upcoming clinical trials in which UBE3A gene expression is reactivated and suggest that even transient UBE3A reinstatement during a critical window of early development is likely to prevent most adverse Angelman syndrome phenotypes. However, sustained UBE3A expression into adulthood is probably needed for optimal clinical benefit.