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Background  Angelman syndrome (AS) is a rare neurodevelopmental disorder caused by the loss of functional ubiquitin protein ligase E3A (UBE3A). In neurons, UBE3A expression is tightly regulated by a mechanism of imprinting which suppresses the expression of the paternal  UBE3A  allele. Promising treatment strategies for AS are directed at activating paternal  UBE3A  gene expression. However, for such strategies to be successful, it is important to know when such a treatment should start, and how much UBE3A expression is needed for normal embryonic brain development.    Methods  Using a conditional mouse model of AS, we further delineated the critical period for UBE3A expression during early brain development.  Ube3a  gene expression was induced around the second week of gestation and mouse phenotypes were assessed using a behavioral test battery. To investigate the requirements of embryonic UBE3A expression, we made use of mice in which the paternal  Ube3a  allele was deleted.    Results  We observed a full behavioral rescue of the AS mouse model phenotypes when  Ube3a  gene reactivation was induced around the start of the last week of mouse embryonic development. We found that full silencing of the paternal  Ube3a  allele was not completed till the first week after birth but that deletion of the paternal  Ube3a  allele had no significant effect on the assessed phenotypes.    Limitations  Direct translation to human is limited, as we do not precisely know how human and mouse brain development aligns over gestational time. Moreover, many of the assessed phenotypes have limited translational value, as the underlying brain regions involved in these tasks are largely unknown.    Conclusions  Our findings provide further important insights in the requirement of UBE3A expression during brain development. We found that loss of up to 50% of UBE3A protein during prenatal mouse brain development does not significantly impact the assessed mouse behavioral phenotypes. Together with previous findings, our results indicate that the most critical function for mouse UBE3A lies in the early postnatal period between birth and P21.

Assessing the requirements of prenatal UBE3A expression for rescue of behavioral phenotypes in a mouse model for Angelman syndrome