Dyshomeostatic modulation of Ca2+-activated K+ channels in a human neuronal model of KCNQ2 encephalopathy
| Autor: | 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 |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
AHP Action Potentials Neurones Stem cells Electroencephalography Malalties neonatals 0302 clinical medicine Homeostatic plasticity disease modeling M-current Biology (General) Induced pluripotent stem cell KCNQ2 Neurons Brain Diseases medicine.diagnostic_test General Neuroscience Afterhyperpolarization General Medicine excitatory neurons Stem Cells and Regenerative Medicine Potassium channel Burst suppression epileptic encephalopathy Excitatory postsynaptic potential Medicine human iPSCs Neonatal diseases Cèl·lules mare Research Article potassium channel Human Pluripotent Stem Cells QH301-705.5 Science Encephalopathy Biology General Biochemistry Genetics and Molecular Biology homeostatic plasticity Cell Line Potassium channels 03 medical and health sciences Canals de potassi medicine Humans KCNQ2 Potassium Channel burst-suppression General Immunology and Microbiology dyshomeostatic medicine.disease 030104 developmental biology nervous system Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Dipòsit Digital de la UB Universidad de Barcelona eLife eLife, Vol 10 (2021) |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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