Augmented Reticular Thalamic Bursting and Seizures in Scn1a-Dravet Syndrome Ritter-Makinson S, Clemente-Perez A, Higashikubo B, Cho FS, Holden SS, Bennett E, Chkhaidze A, Eelkman Rooda OHJ, Cornet MC, Hoebeek FE, Yamakawa K, Cilio MR, Delord B, Paz JT. Cell Rep. 2019;26(1):54-64.e6. doi:10.1016/j.celrep.2018.12.018. Loss of function in the Scn1a gene leads to a severe epileptic encephalopathy called Dravet syndrome (DS). Reduced excitability in cortical inhibitory neurons is thought to be the major cause of DS seizures. Here, in contrast, we show enhanced excitability in thalamic inhibitory neurons that promotes the nonconvulsive seizures that are a prominent yet poorly understood feature of DS. In a mouse model of DS with a loss of function in Scn1a, reticular thalamic cells exhibited abnormally long bursts of firing caused by the downregulation of calcium-activated potassium SK channels. Our study supports a mechanism in which loss of SK activity causes the reticular thalamic neurons to become hyperexcitable and promote nonconvulsive seizures in DS. We propose that reduced excitability of inhibitory neurons is not global in DS and that non-GABAergic mechanisms such as SK channels may be important targets for treatment.

中文翻译：

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靶向补偿性离子通道基因表达是否是Dravet综合征的可行治疗策略？

Scn1a-Dravet综合征Ritter-Makinson S，Clemente-Perez A，Higashikubo B，Cho FS，Holden SS，Bennett E，Chkhaidze A，Eelkman Rooda OHJ，Cornet MC，Hoebeek FE，Yamakawa K，Cilio增强的网状丘脑爆裂和癫痫发作MR，Delord B，Paz JT。Cell Rep.2019; 26（1）：54-64.e6。doi：10.1016 / j.celrep.2018.12.018。Scn1a基因功能丧失会导致严重的癫痫性脑病，称为Dravet综合征（DS）。皮质抑制神经元的兴奋性降低被认为是DS癫痫发作的主要原因。在这里，相比之下，我们在丘脑抑制神经元中表现出增强的兴奋性，从而促进了非惊厥性癫痫发作，这是DS的一个突出但尚未广为人知的特征。在Scn1a中失去功能的DS鼠标模型中，网状丘脑细胞表现出异常长时间的放电，这是由于钙激活的钾SK通道的下调引起的。我们的研究支持一种机制，其中SK活性丧失导致网状丘脑神经元变得过度兴奋并促进DS中非惊厥性癫痫发作。我们建议抑制性神经元的兴奋性降低在DS中并不普遍，并且非GABA能机制（例如SK通道）可能是治疗的重要目标。