Format

Send to

Choose Destination
Science. 2019 Dec 20;366(6472):1486-1492. doi: 10.1126/science.aav5386.

Potassium channel dysfunction in human neuronal models of Angelman syndrome.

Author information

1
National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore. sunxya@gis.a-star.edu.sg shawn.je@duke-nus.edu.sg.
2
Genome Institute of Singapore, 60 Biopolis Street, Singapore 138672, Singapore.
3
Graduate School for Integrative Sciences and Engineering, National University of Singapore, 28 Medical Drive, Singapore 117456, Singapore.
4
Signature Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore.
5
Department of Neurobiology, Duke University School of Medicine, Durham, NC 27710, USA.
6
National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore.
7
Department of Biomedical Engineering, National University of Singapore, Singapore 117576, Singapore.
8
Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore.
9
Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, 8 College Road, 169857, Singapore.
10
Singapore Bioimaging Consortium, Agency for Science Technology and Research (A*STAR), Singapore 138667, Singapore.
11
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.
12
Lee Kong Chian School of Medicine, Nanyang Technological University, 11 Mandalay Road, Singapore 308232, Singapore.
13
Signature Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore. sunxya@gis.a-star.edu.sg shawn.je@duke-nus.edu.sg.
#
Contributed equally

Abstract

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. BK 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.

PMID:
31857479
DOI:
10.1126/science.aav5386

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center