Dravet Syndrome (DS) is a severe developmental epileptic encephalopathy with frequent intractable seizures accompanied by cognitive impairment, often caused by pathogenic variants in SCN1A encoding sodium channel NaV1.1. Recent research utilizing in vitro patient-derived neuronal networks and accompanying in silico models uncovered that not just sodium—but also potassium—and synaptic currents were impaired in DS networks. Here, we explore the implications of these findings for three questions that remain elusive in DS: How do sodium channel impairments result in epilepsy? How can identical variants lead to varying phenotypes? What mechanisms underlie the developmental delay in DS patients? We speculate that impaired potassium currents might be a secondary effect to NaV1.1 mutations and could result in hyperexcitable neurons and epileptic networks. Moreover, we reason that homeostatic plasticity is actively engaged in DS networks, possibly affecting the phenotype and impairing learning and development when driven to extremes.

中文翻译：

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解开 Dravet 综合征：探索钠通道突变对神经元网络的复杂影响

Dravet 综合征 (DS) 是一种严重的发育性癫痫性脑病，伴有频繁的顽固性癫痫发作并伴有认知障碍，通常由编码钠通道 Na 的 SCN1A 的致病性变异引起V1.1. 最近的研究利用体外患者来源的神经元网络和相应的计算机模型发现，DS 网络中不仅钠，而且钾和突触电流都受到损害。在这里，我们探讨这些发现对 DS 中仍然难以捉摸的三个问题的影响：钠通道损伤如何导致癫痫？相同的变异如何导致不同的表型？DS 患者发育迟缓的机制是什么？我们推测钾电流受损可能是钠的继发效应V1.1 突变，可能导致神经元和癫痫网络过度兴奋。此外，我们推断稳态可塑性积极参与 DS 网络，当走向极端时可能会影响表型并损害学习和发展。