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Dyshomeostatic modulation of Ca2+-activated K+ channels in a human neuronal model of KCNQ2 encephalopathy

Authors :
Steven J. Lubbe
Gabriella L Robertson
Carlos G. Vanoye
Reshma R. Desai
Peter Penzes
John Millichap
Evangelos Kiskinis
Bernabé I. Bustos
Kelly A Marshall
Dina Simkin
Brandon N Piyevsky
Alfred L. George
Juan A. Ortega
Linda Laux
Marc P. Forrest
Source :
Dipòsit Digital de la UB, Universidad de Barcelona, eLife, eLife, Vol 10 (2021)
Publication Year :
2021
Publisher :
eLife Sciences, 2021.

Abstract

Mutations in KCNQ2, which encodes a pore-forming K+ channel subunit responsible for neuronal M-current, cause neonatal epileptic encephalopathy, a complex disorder presenting with severe early-onset seizures and impaired neurodevelopment. The condition is exceptionally difficult to treat, partially because the effects of KCNQ2 mutations on the development and function of human neurons are unknown. Here, we used induced pluripotent stem cells (iPSCs) and gene editing to establish a disease model and measured the functional properties of differentiated excitatory neurons. We find that patient iPSC-derived neurons exhibit faster action potential repolarization, larger post-burst afterhyperpolarization and a functional enhancement of Ca2+-activated K+ channels. These properties, which can be recapitulated by chronic inhibition of M-current in control neurons, facilitate a burst-suppression firing pattern that is reminiscent of the interictal electroencephalography pattern in patients. Our findings suggest that dyshomeostatic mechanisms compound KCNQ2 loss-of-function leading to alterations in the neurodevelopmental trajectory of patient iPSC-derived neurons.

Details

Database :
OpenAIRE
Journal :
Dipòsit Digital de la UB, Universidad de Barcelona, eLife, eLife, Vol 10 (2021)
Accession number :
edsair.doi.dedup.....7bb3f591130ed352737002c9c4ded72b