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Abstract：
Loss-of-function variants in the gene SCN2A, which encodes the sodium channel NaV1.2, are strongly associated with autism spectrum disorder and intellectual disability. An estimated 20%-30% of children with these variants also suffer from epilepsy, with altered neuronal activity originating in neocortex, a region where NaV1.2 channels are expressed predominantly in excitatory pyramidal cells. This is paradoxical, as sodium channel loss in excitatory cells would be expected to dampen neocortical activity rather than promote seizure. Here, we examined pyramidal neurons lacking NaV1.2 channels and found that they were intrinsically hyperexcitable, firing high-frequency bursts of action potentials (APs) despite decrements in AP size and speed. Compartmental modeling and dynamic-clamp recordings revealed that NaV1.2 loss prevented potassium channels from properly repolarizing neurons between APs, increasing overall excitability by allowing neurons to reach threshold for subsequent APs more rapidly. This cell-intrinsic mechanism may, therefore, account for why SCN2A loss-of-function can paradoxically promote seizure.
摘要：
基因SCN2A的功能缺失变异，它编码钠通道NaV1.2，与自闭症谱系障碍和智力障碍密切相关。估计有20％-30％的这些变异的儿童也患有癫痫，新皮层的神经元活动改变，NaV1.2通道主要在兴奋性锥体细胞中表达的区域。这是自相矛盾的,因为兴奋性细胞中钠通道的丢失预计会抑制新皮质活动，而不是促进癫痫发作。这里,我们检查了缺乏NaV1.2通道的锥体神经元，发现它们本质上是过度兴奋的，尽管AP的大小和速度都在减少，但仍会激发高频动作电位（AP）。隔室建模和动态钳夹记录显示，NaV1.2丢失阻止钾通道在AP之间正常复极化神经元，通过允许神经元更快地达到后续AP的阈值来增加整体兴奋性。这种细胞内在机制可能，因此,解释为什么SCN2A功能丧失会矛盾地促进癫痫发作。
