Dyshomeostatic modulation of Ca 2+ -activated K + channels in a human neuronal model of KCNQ2 encephalopathy

Mutations in , 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 becaus...

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Bibliographic Details
Published ineLife Vol. 10
Main Authors Simkin, Dina, Marshall, Kelly A, Vanoye, Carlos G, Desai, Reshma R, Bustos, Bernabe I, Piyevsky, Brandon N, Ortega, Juan A, Forrest, Marc, Robertson, Gabriella L, Penzes, Peter, Laux, Linda C, Lubbe, Steven J, Millichap, John J, George, Jr, Alfred L, Kiskinis, Evangelos
Format Journal Article
LanguageEnglish
Published England 05.02.2021
Subjects
Action Potentials - physiology
Brain Diseases - genetics
Brain Diseases - physiopathology
Cell Line
Humans
KCNQ2 Potassium Channel - genetics
KCNQ2 Potassium Channel - metabolism
Neurons - physiology
Pluripotent Stem Cells
stem cells
neuroscience
regenerative medicine
disease modeling
AHP
burst-suppression
excitatory neurons
human iPSCs
epileptic encephalopathy
M-current
homeostatic plasticity
KCNQ2
potassium channel
dyshomeostatic
human
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Summary:Mutations in , 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 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 Ca -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.
ISSN:2050-084X