Department of Biological Sciences, Korea Advanced Institute for Science and Technology (KAIST), Daejeon, 34141, Korea.
Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon, 34141, Korea.
Nat Commun. 2023 Jun 15;14(1):3547. doi: 10.1038/s41467-023-39203-z.
Autism spectrum disorders (ASD) represent neurodevelopmental disorders characterized by social deficits, repetitive behaviors, and various comorbidities, including epilepsy. ANK2, which encodes a neuronal scaffolding protein, is frequently mutated in ASD, but its in vivo functions and disease-related mechanisms are largely unknown. Here, we report that mice with Ank2 knockout restricted to cortical and hippocampal excitatory neurons (Ank2-cKO mice) show ASD-related behavioral abnormalities and juvenile seizure-related death. Ank2-cKO cortical neurons show abnormally increased excitability and firing rate. These changes accompanied decreases in the total level and function of the Kv7.2/KCNQ2 and Kv7.3/KCNQ3 potassium channels and the density of these channels in the enlengthened axon initial segment. Importantly, the Kv7 agonist, retigabine, rescued neuronal excitability, juvenile seizure-related death, and hyperactivity in Ank2-cKO mice. These results suggest that Ank2 regulates neuronal excitability by regulating the length of and Kv7 density in the AIS and that Kv7 channelopathy is involved in Ank2-related brain dysfunctions.
自闭症谱系障碍（ASD）是一种神经发育障碍，其特征是社交缺陷、重复行为和各种合并症，包括癫痫。ANK2 编码一种神经元支架蛋白，在 ASD 中经常发生突变，但它的体内功能和与疾病相关的机制在很大程度上是未知的。在这里，我们报告说，局限于皮质和海马兴奋性神经元的 Ank2 敲除小鼠（Ank2-cKO 小鼠）表现出与 ASD 相关的行为异常和青少年期与癫痫相关的死亡。Ank2-cKO 皮质神经元表现出异常增加的兴奋性和放电率。这些变化伴随着 Kv7.2/KCNQ2 和 Kv7.3/KCNQ3 钾通道的总水平和功能以及这些通道在延长的轴突起始段的密度降低。重要的是，Kv7 激动剂 retigabine 挽救了 Ank2-cKO 小鼠的神经元兴奋性、青少年期与癫痫相关的死亡和过度活跃。这些结果表明，ANK2 通过调节 AIS 的长度和 Kv7 密度来调节神经元兴奋性，并且 Kv7 通道病与 Ank2 相关的脑功能障碍有关。
Zotero 插件
