Prominent role of forebrain excitatory neurons in SCN8A encephalopathy. Bunton-Stasyshyn RKA, Wagnon JL, Wengert ER, Barker BS, Faulkner A, Wagley PK, Bhatia K, Jones JM, Maniaci MR, Parent JM, Goodkin HP, Patel MK, Meisler MH. Brain. 2019;142(2):362-375. doi:10.1093/brain/awy324. De novo mutations of the sodium channel gene SCN8A result in an epileptic encephalopathy with refractory seizures, developmental delay, and elevated risk of sudden death. p.Arg1872Trp is a recurrent de novo SCN8A mutation reported in 14 unrelated individuals with epileptic encephalopathy that included seizure onset in the prenatal or infantile period and severe verbal and ambulatory comorbidities. The major biophysical effect of the mutation was previously shown to be impaired channel inactivation accompanied by increased current density. We have generated a conditional mouse mutation in which expression of this severe gain-of-function mutation is dependent upon Cre recombinase. Global activation of p.Arg1872Trp by EIIa-Cre resulted in convulsive seizures and lethality at 2 weeks of age. Neural activation of the p.Arg1872Trp mutation by Nestin-Cre also resulted in early-onset seizures and death. Restriction of p.Arg1872Trp expression to excitatory neurons using Emx1-Cre recapitulated seizures and juvenile lethality between 1 and 2 months of age. In contrast, activation of p.Arg1872Trp in inhibitory neurons by Gad2-Cre or Dlx5/6-Cre did not induce seizures or overt neurological dysfunction. The sodium channel modulator GS967/Prax330 prolonged survival of mice with global expression of R1872W and also modulated the activity of the mutant channel in transfected cells. Activation of the p.Arg1872Trp mutation in adult mice was sufficient to generate seizures and death, indicating that successful therapy will require lifelong treatment. These findings provide insight into the pathogenic mechanism of this gain-of-function mutation of SCN8A and identify excitatory neurons as critical targets for therapeutic intervention.

中文翻译：

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SCN8A：当神经元如此兴奋时，他们就无法隐藏它。

前脑兴奋性神经元在SCN8A脑病中的重要作用。Bunton-Stasyshyn RKA，Wagnon JL，Wengert ER，Barker BS，Faulkner A，Wagley PK，Bhatia K，Jones JM，Maniaci MR，父母JM，Goodkin HP，Patel MK，Meisler MH。脑。2019; 142（2）：362-375。doi：10.1093 /大脑/ awy324。钠通道基因SCN8A的从头突变导致癫痫性脑病，伴有难治性癫痫发作，发育迟缓和猝死风险升高。p.Arg1872Trp是一种从头发生的复发性SCN8A突变，在14名无关的癫痫性脑病患者中报道，包括产前或婴儿期发作和严重的言语和非卧床合并症。先前已证明，突变的主要生物物理作用是通道失活受损，并伴随着电流密度增加。我们已经生成了条件小鼠突变，其中这种严重的功能获得性突变的表达依赖于Cre重组酶。EIIa-Cre对p.Arg1872Trp的整体激活导致2周龄惊厥性癫痫发作和致死性。Nestin-Cre对p.Arg1872Trp突变的神经激活也导致早发性癫痫发作和死亡。使用Emx1-Cre重现癫痫发作和1至2个月大的幼年杀伤力，可将p.Arg1872Trp表达限制于兴奋性神经元。相反，Gad2-Cre或Dlx5 / 6-Cre在抑制性神经元中激活p.Arg1872Trp不会引起癫痫发作或明显的神经功能障碍。钠通道调节剂GS967 / Prax330延长了具有R1872W整体表达的小鼠的存活，并且还调节了转染细胞中突变通道的活性。成年小鼠中p.Arg1872Trp突变的激活足以引起癫痫发作和死亡，这表明成功的治疗将需要终生治疗。这些发现为SCN8A功能获得性突变的致病机理提供了见识，并确定了兴奋性神经元是治疗干预的关键靶标。