Journal
SCIENCE
Volume 366, Issue 6472, Pages 1486-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aav5386
Keywords
-
Categories
Funding
- Singapore Ministry of Education (MOE) [MOE2014-T2-2-071]
- National Medical Research Council [NMRC/OFIRG/0050/2017]
- KHOO Bridge funding [Duke-NUS-KBrFA/2017/0004]
- Duke-NUS Signature Research Program block grant
- Khoo Postdoctoral Fellowship Award [Duke-NUS-KPFA/2016/0007]
- National Parkinson's Disease Translational Clinical Research Program fund [NMRC/TCR/013-NNI/2014]
- Singapore Translational Research Investigator Award [NMRC/STaR/014/2013]
- NMRC [NMRC/OFYIRG/0022/2016]
Ask authors/readers for more resources
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 calciumand 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available