Impaired M-current in KCNQ2 Encephalopathy Evokes Dyshomeostatic Modulation of Excitability

摘要: ABSTRACT Mutations in KCNQ2, which encodes a pore-forming K+ channel subunit responsible for neuronal M-current, cause neonatal epileptic encephalopathy, 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 development function human neurons are unknown. Here, we used induced pluripotent stem cells gene editing establish disease model, measured functional properties patient-derived using electrophysiological optical approaches. We find that while excitatory exhibit reduced M-current early, they develop intrinsic network hyperexcitability progressively. This associated faster action potential repolarization, larger afterhyperpolarization, enhancement large conductance Ca2+-activated (BK) channels. These facilitate burst-suppression firing pattern reminiscent interictal electroencephalography patients. Importantly, were able phenocopy these excitability features control only by chronic but not acute pharmacological inhibition M-current. Our findings suggest dyshomeostatic mechanisms compound loss-of-function lead alterations neurodevelopmental trajectory neurons. work has therapeutic implications explaining why agonists beneficial unless started at an early stage.