Numerous targets of Ube3a-dependent ubiquitination have been identified (Kumar et al., 1999; Mani et al., 2006; Mulherkar et al., 2009; Louria-Hayon et al., 2009; Zaaroor-Regev et al., 2010) in attempts to dissect the molecular mechanisms underlying Angelman syndrome. One target is activity-regulated cytoskeleton protein (Arc), which promotes the internalization of AMPA receptors, and is interesting considering the functional defect of AMPA receptor mediated synaptic transmission (Greer et al., 2010). More recent evidence suggests that Ube3a regulates Arc expression through estradiol-induced transcription rather than through ubiquitination (Kühnle et al., 2013). Recent findings also indicate that in Drosophila Ube3a acts as a cofactor for some MeCP2 functions (Kim et al., 2013) and Ube3am−/p+ mice demonstrate deficits in BDNF signaling (Cao et al., 2013). Additionally, Ube3am−/p+ mice have presynaptic vesicle cycling defects specifically in inhibitory interneurons (Wallace et al., 2012). These observations clearly demand further investigation on some very basic questions. For instance, is the dosage of Ube3a in excitatory or inhibitory neurons responsible for the profound neurobehavioral impairment? Moreover, is the dosage of Ube3a primarily affecting pre- or postsynaptic sites?
