How Many Angels Can Dance on the Head of a Patch Pipette? Understanding Neuronal Hyperexcitability in Angelman Syndrome

Potassium Channel Dysfunction in Human Neuronal Models of Angelman Syndrome Sun AX, Yuan Q, Fukuda M, Yu W, Yan H, Lim GGY, Nai MH, D’Agostino GA, Tran H-D, Itahana Y, Wang D, Lokman H, Itahana K, Lim SWL, Tang J, Chang YY, Zhang M, Cook SA, Rackham OJL, Lim CT, Tan EK, Ng HH, Lim KL, Jiang Y-H, Je HS. Science. 2019;366(6472):1486-1492. doi: 10.1126/science.aav5386 Disruptions in the ubiquitin protein ligase E3A (UBE3A) gene cause Angelman syndrome (AS). Whereas AS model mice have associated synaptic dysfunction and altered plasticity with abnormal behavior, whether similar or other mechanisms contribute to network hyperactivity and epilepsy susceptibility in AS patients remains unclear. Using human neurons and brain organoids, we demonstrate that UBE3A suppresses neuronal hyperexcitability via ubiquitin-mediated degradation of calcium and voltage-dependent big potassium (BK) channels. We provide evidence that augmented BK channel activity manifests as increased intrinsic excitability in individual neurons and subsequent network synchronization. Big potassium antagonists normalized neuronal excitability in both human and mouse neurons and ameliorated seizure susceptibility in an AS mouse model. Our findings suggest that BK channelopathy underlies epilepsy in AS and support the use of human cells to model human developmental diseases.