Tuesday, May 17, 2022
5/17/2022
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.
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