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Title: Dyshomeostatic modulation of Ca2+-activated K+ channels in a human neuronal model of KCNQ2 encephalopathy
Author: Simkin, Dina
Marshall, Kelly A.
Vanoye, Carlos G.
Desai, Reshma R.
Bustos, Bernabe I.
Piyevsky, Brandon N.
Ortega Cano, Juan Alberto
Forrest, Marc
Robertson, Gabriella L.
Penzes, Peter
Laux, Linda C.
Lubbe, Steven J.
Millichap, John J.
George Jr, Alfred L.
Kiskinis, Evangelos
Keywords: Canals de potassi
Cèl·lules mare
Malalties neonatals
Potassium channels
Stem cells
Neonatal diseases
Issue Date: 5-Feb-2021
Publisher: eLife Sciences
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.
Note: Reproducció del document publicat a:
It is part of: eLife, 2021
Related resource:
ISSN: 2050-084X
Appears in Collections:Articles publicats en revistes (Patologia i Terapèutica Experimental)

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