Department of Neuroscience and Cell Biology, Graduate School of Medicine, Osaka University, Suita, 565-0871, Japan; United Graduate School of Child Development, Osaka University, Suita, 565-0871, Japan; Global Center for Medical Engineering and Informatics, Osaka University, Suita, 565-0871, Japan; Addiction Research Unit, Osaka Psychiatric Research Center, Osaka Psychiatric Medical Center, Hirakata, 573-0022, Japan.
Department of Child Development and Molecular Brain Science, United Graduate School of Child Development, Osaka University, Suita, 565-0871, Japan.
Neurochem Int. 2022 Feb;153:105273. doi: 10.1016/j.neuint.2021.105273. Epub 2021 Dec 28.
The axon initial segment (AIS) is a structural neuronal compartment of the proximal axon that plays key roles in sodium channel clustering, action potential initiation, and signal propagation of neuronal outputs. Mutations in constitutive genes of the AIS, such as ANK3, have been identified in patients with neurodevelopmental disorders. Nevertheless, morphological changes in the AIS in neurodevelopmental disorders have not been characterized. In this study, we investigated the length of the AIS in rodent models of attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). We observed abnormalities in AIS length in both animal models. In ADHD model rodents, we observed shorter AIS length in layer 2/3 (L2/3) neurons of the medial prefrontal cortex (mPFC) and primary somatosensory barrel field (S1BF). Further, we observed shorter AIS length in S1BF L5 neurons. In ASD model mice, we observed shorter AIS length in L2/3 and L5 neurons of the S1BF. These results suggest that impairments in AIS length are common phenomena in neurodevelopmental disorders such as ADHD and ASD and may be conserved across species. Our findings provide novel insight into the potential contribution of the AIS to the pathophysiology and pathogenesis of neurodevelopmental disorders.
轴突起始段（AIS）是近端轴突的一种结构神经元区室，在钠通道聚类、动作电位起始和神经元输出信号传递中发挥关键作用。在神经发育障碍患者中已经鉴定出 AIS 的组成性基因，如 ANK3 的突变。然而，神经发育障碍中的 AIS 形态变化尚未得到表征。在这项研究中，我们研究了注意力缺陷多动障碍（ADHD）和自闭症谱系障碍（ASD）的啮齿动物模型中的 AIS 长度。我们观察到这两种动物模型中的 AIS 长度都存在异常。在 ADHD 模型啮齿动物中，我们观察到内侧前额叶皮层（mPFC）和初级体感桶状皮层（S1BF）的 L2/3 神经元的 AIS 长度缩短。此外，我们还观察到 S1BF L5 神经元的 AIS 长度缩短。在 ASD 模型小鼠中，我们观察到 S1BF 的 L2/3 和 L5 神经元的 AIS 长度缩短。这些结果表明，AIS 长度的损伤是 ADHD 和 ASD 等神经发育障碍的常见现象，并且可能在物种间保守。我们的发现为 AIS 对神经发育障碍的病理生理学和发病机制的潜在贡献提供了新的见解。
