Dysfunction in sodium channels and their ankyrin scaffolding partners have both been implicated in neurodevelopmental disorders, including autism spectrum disorder (ASD). In particular, the genes , which encodes the sodium channel Na1.2, and , which encodes ankyrin-B, have strong ASD association. Recent studies indicate that ASD-associated haploinsufficiency in impairs dendritic excitability and synaptic function in neocortical pyramidal cells, but how Na1.2 is anchored within dendritic regions is unknown. Here, we show that ankyrin-B is essential for scaffolding Na1.2 to the dendritic membrane of mouse neocortical neurons and that haploinsufficiency of phenocopies intrinsic dendritic excitability and synaptic deficits observed in conditions. These results establish a direct, convergent link between two major ASD risk genes and reinforce an emerging framework suggesting that neocortical pyramidal cell dendritic dysfunction can contribute to neurodevelopmental disorder pathophysiology.

中文翻译：

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新皮质锥体细胞树突中自闭症风险基因 Scn2a 和 Ank2 的物理和功能趋同

钠通道及其锚蛋白支架伙伴的功能障碍都与神经发育障碍有关，包括自闭症谱系障碍（ASD）。特别是，编码钠通道 Na1.2 的基因 和编码锚蛋白-B 的基因与 ASD 具有很强的关联性。最近的研究表明，ASD 相关的单倍体不足会损害新皮质锥体细胞的树突兴奋性和突触功能，但 Na1.2 如何锚定在树突区域内尚不清楚。在这里，我们表明锚蛋白-B 对于将 Na1.2 支架固定到小鼠新皮质神经元的树突膜至关重要，并且表型的单倍体不足反映了在条件下观察到的固有树突兴奋性和突触缺陷。这些结果在两个主要 ASD 风险基因之间建立了直接、趋同的联系，并强化了一个新兴框架，表明新皮质锥体细胞树突功能障碍可能导致神经发育障碍病理生理学。