The Ken & Ruth Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, United States.
Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, United States.
Elife. 2021 Feb 5;10:e64434. doi: 10.7554/eLife.64434.
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.
编码负责神经元 M 电流的孔形成 K 通道亚基的基因突变可导致新生儿癫痫性脑病，这是一种复杂的疾病，表现为严重的早发性癫痫发作和神经发育受损。这种情况极难治疗，部分原因是 基因突变对人类神经元发育和功能的影响尚不清楚。在这里，我们使用诱导多能干细胞（iPSC）和基因编辑建立疾病模型，并测量分化兴奋性神经元的功能特性。我们发现，患者的 iPSC 衍生神经元表现出更快的动作电位复极化、更大的爆发后超极化以及钙激活的 K 通道功能增强。这些特性可以通过慢性抑制对照神经元中的 M 电流来重现，促进爆发抑制放电模式，类似于患者的癫痫间脑电图模式。我们的研究结果表明，神经发育轨迹的改变是由于 KCNQ2 功能丧失导致的神经动态失衡机制的复合作用。
