MODELLING ANGELMAN SYNDROME WITH INDUCED HUMAN NEURONS

Abstract

Disruptions of the UBE3A gene cause Angelman syndrome (AS). While mouse models of AS have associated synaptic dysfunction and altered plasticity with abnormal behaviour, whether similar, or other mechanisms, contribute to network hyperactivity and increased epilepsy susceptibility in AS patients remains unclear. In this project, by utilizing human neurons and brain organoids, we identified a novel role for UBE3A whereby it suppresses neuronal hyperexcitability via the ubiquitin-mediated degradation of BK channels. We further demonstrated that augmented BK channel activity manifests as increased intrinsic excitability in individual neurons and subsequently network synchronization, and that these effects could be normalized by BK antagonists. Our study suggests BK channelopathy underlies AS, and more broadly speaks to the necessity of using human cells for functional interrogation of human developmental diseases.