A deleterious Nav1.1 mutation selectively impairs telencephalic inhibitory neurons derived from Dravet Syndrome patients
A deleterious Nav1.1 mutation selectively impairs telencephalic inhibitory neurons derived from Dravet Syndrome patients
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DOI：
10.7554/elife.13073
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发表时间：
2016-07-26
期刊：
影响因子：
7.7
通讯作者：
Dolmetsch, Ricardo E.
中科院分区：
文献类型：
--
作者：
Sun, Yishan;Pasca, Sergiup P.;Dolmetsch, Ricardo E.
Dravet综合征是一种与SCN 1A（编码神经元钠通道Na（v）1.1的基因）有害突变相关的儿童癫痫的难治性形式。早期使用人类诱导多能干细胞（iPSC）的研究已经产生了关于Nav1.1在人类抑制性神经元与兴奋性神经元中的重要性的混合结果。我们研究了在一对Dravet综合征双胞胎中发现的Nav1.1突变（p.S1328P），并从这些患者中产生了iPSC衍生的神经元。突变体通道的表征揭示了电流幅度的降低和对稳态失活的超敏性。然后，我们将Dravet综合征和对照iPSC分化为端脑兴奋性神经元或内侧神经节隆起（MGE）样抑制性神经元。Dravet抑制性神经元表现出钠电流和动作电位放电的缺陷，这是由Nav1.1转基因拯救的，而Dravet兴奋性神经元是正常的。我们的研究确定了有害的Nav1.1突变的生物物理损伤，并支持Dravet综合征由缺陷的抑制性神经元引起的假设。
Dravet Syndrome is an intractable form of childhood epilepsy associated with deleterious mutations in SCN1A, the gene encoding neuronal sodium channel Na(v)1.1. Earlier studies using human induced pluripotent stem cells (iPSCs) have produced mixed results regarding the importance of Nav1.1 in human inhibitory versus excitatory neurons. We studied a Nav1.1 mutation (p.S1328P) identified in a pair of twins with Dravet Syndrome and generated iPSC-derived neurons from these patients. Characterization of the mutant channel revealed a decrease in current amplitude and hypersensitivity to steady-state inactivation. We then differentiated Dravet-Syndrome and control iPSCs into telencephalic excitatory neurons or medial ganglionic eminence (MGE)-like inhibitory neurons. Dravet inhibitory neurons showed deficits in sodium currents and action potential firing, which were rescued by a Nav1.1 transgene, whereas Dravet excitatory neurons were normal. Our study identifies biophysical impairments underlying a deleterious Nav1.1 mutation and supports the hypothesis that Dravet Syndrome arises from defective inhibitory neurons.