Dyshomeostatic modulation of ca2+-activated k+ channels in a human neuronal model of kcnq2 encephalopathy

Dina Simkin, Kelly A. Marshall, Carlos G. Vanoye, Reshma R. Desai, Bernabe I. Bustos, Brandon N. Piyevsky, Juan A. Ortega, Marc Forrest, Gabriella L. Robertson, Peter Penzes, Linda C. Laux, Steven J. Lubbe, John J. Millichap, Alfred L. George*, Evangelos Kiskinis

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article numbere64434
Pages (from-to)1-32
Number of pages32
JournaleLife
Volume10
DOIs
StatePublished - Feb 2021

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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