Abstract/Summary
Angelman syndrome (AS) is a rare neurodevelopmental disorder with severe developmental
delay, lack of language skills, severe cognitive impairment, motor dysfunctionand sleep disorder,
and AS patients often have comorbid epilepsy and autism. Genetic/genomic studies have
attributed impaired expression of UBE3A in neurons as the cause of AS. Recent studies have
also identified the mechanism underlying paternal Ube3a gene silencing and the potential of
providing a cure for AS through the unsilencing of the paternal UBE3A gene, thereby restoring
UBE3A. While this has generated tremendous excitement in the AS community, animal research
has also shown that for most phenotypes, the unsilencing of the UBE3A gene has to occur
immediately after birth. Intriguingly, although restoring Ube3a in AS mice in adulthood rescued
contextual memory of fear conditioning, it did not affect motor function impairment or abnormal
anxiety behaviors. Furthermore, over-expression of UBE3A has been implicated in autism
spectrum disorder (ASD), which underscores the tight regulation of UBE3A expression. Thus,
there is still an urgent need for further understanding the function of UBE3A and the
pathophysiology of AS. We recently showed that Ube3a ubiquitinates SK2, a Ca2+-activated small
conductance potassium channel and facilitates its removal from excitatory synapses by
endocytosis and subsequent degradation. Subsequently, we showed that Ube3a-mediated SK2
ubiquitination not only results in its endocytosis, but also inhibits its recycling back to synaptic
membranes, and that PKA and Ube3a jointly regulate synaptic SK2 levels. SK2 channels have
been shown to play important roles in diverse brain functions, including learning and memory,
mood regulation, motor function and rhythmic activities, etc. Our long-term goals are to better
understand AS pathogenesis in order to develop potential therapeutic strategies. Our immediate
goal in the proposed studies is directed at determining the roles of Ube3a- and PKA-mediated
regulation of synaptic SK2 levels in the amygdala, specifically in auditory fear learning and fear
memory recall. We will also test whether enhanced neural intrinsic excitability during one learning
episode facilitates learning in a second learning episode, which could improve auditory fear
learning in AS mice, and lead to potential translational applications in AS patients. The proposed
studies will also provide high value-added learning experiences and promote scholarly activity for
students and faculty at our university.