Angelman syndrome is a neurodevelopmental disorder caused by mutations in the maternally inherited UBE3A gene, which encodes a ubiquitin ligase. Greer et al. (2010) now identify a UBE3A substrate called Arc that promotes endocytosis of neuronal AMPA receptors, providing insight into synaptic defects that may underlie the cognitive deficits in Angelman syndrome. Angelman syndrome is a neurodevelopmental disorder caused by mutations in the maternallyinherited UBE3A gene, which encodes a ubiquitin ligase. Greer et al. (2010) now identify a UBE3Asubstrate called Arc that promotes endocytosis of neuronal AMPA receptors, providing insight intosynaptic defects that may underlie the cognitive deficits in Angelman syndrome.