PDF(Pubmed)
Abstract：
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 SCN2A, which encodes the sodium channel NaV1.2, and ANK2, which encodes ankyrin-B, have strong ASD association. Recent studies indicate that ASD-associated haploinsufficiency in Scn2a impairs dendritic excitability and synaptic function in neocortical pyramidal cells, but how NaV1.2 is anchored within dendritic regions is unknown. Here, we show that ankyrin-B is essential for scaffolding NaV1.2 to the dendritic membrane of mouse neocortical neurons and that haploinsufficiency of Ank2 phenocopies intrinsic dendritic excitability and synaptic deficits observed in Scn2a+/- 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.
摘要：
钠通道的功能障碍及其锚蛋白支架伴侣都与神经发育障碍有关，包括自闭症谱系障碍（ASD）。特别是,基因SCN2A，它编码钠通道NaV1.2和ANK2，它编码Anyrin-B，有很强的ASD协会。最近的研究表明，Scn2a中与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NaV1.2如何锚定在树突区域是未知的。这里,我们表明，ankyrin-B对于将NaV1.2支架固定到小鼠新皮质神经元的树突膜至关重要，并且Ank2表型的单倍体功能不足会在Scn2a/-条件下观察到固有的树突兴奋性和突触缺陷。这些结果建立了一个直接的，两个主要ASD风险基因之间的融合联系，并加强了一个新兴的框架，表明新皮质锥体细胞树突状功能障碍可能导致神经发育障碍的病理生理学。
