Concussive Head Trauma Deranges Axon Initial Segment Function in Axotomized and Intact Layer 5 Pyramidal Neurons.
Concussive Head Trauma Deranges Axon Initial Segment Function in Axotomized and Intact Layer 5 Pyramidal Neurons.
复制标题
头部震荡创伤扰乱轴突初始段功能，轴突和完整的第 5 层锥体神经元。
DOI：
10.1089/neu.2022.0469
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发表时间：
2024
影响因子：
4.2
通讯作者：
Jacobs,KimberleM
中科院分区：
文献类型：
--
作者：
HarrisJr,AlanC;Sun,Jianli;Jacobs,KimberleM
轴突起始段（AIS）是控制动作电位（AP）产生和神经元信息合成的关键部位。脑震荡创伤引起弥漫性轴索切断，大多数新皮质轴索损伤发生在AIS。因此，震荡性创伤性脑损伤可能会严重破坏该区域的功能特化。为了研究这一假设，在Thy 1-YFP-H小鼠轻度中枢液压冲击损伤后1天和2天，我们记录了来自轴突切断的和相邻的完整的第5层锥体神经元的高分辨率AP，并应用二阶导数（2 o）分析来测量AIS和胞体区域对AP上行的贡献。从假手术动物记录的所有第5层锥体神经元表现出两个由负的干预斜率分开的斯塔克2峰。与此相反，在受伤的小鼠，我们发现了一个亚组的轴突切断层5锥体神经元，其中AIS区域2 opeak被废除，功能扰动与减少兴奋性，轴突发芽和膨胀的AIS作为评估染色ankrex-G。我们的分析揭示了一个额外的亚群的轴突切断和完整的第5层锥体神经元，表现出融合在一起的AIS和胞体区域2峰，这表明更微妙的钠通道功能和/或易位的AIS起始区更接近索马。当在亲环蛋白-D被敲除的动物中重复这些实验时，这些效应得到改善，表明创伤诱导的AIS功能扰动与线粒体钙调节异常相关。
The axon initial segment (AIS) is a critical locus of control of action potential (AP) generation and neuronal information synthesis. Concussive traumatic brain injury gives rise to diffuse axotomy, and the majority of neocortical axonal injury arises at the AIS. Consequently, concussive traumatic brain injury might profoundly disrupt the functional specialization of this region. To investigate this hypothesis, one and two days after mild central fluid percussion injury in Thy1-YFP-H mice, we recorded high-resolution APs from axotomized and adjacent intact layer 5 pyramidal neurons and applied a second derivative (2o) analysis to measure the AIS- and soma-regional contributions to the AP upstroke. All layer 5 pyramidal neurons recorded from sham animals manifested two stark 2opeaks separated by a negative intervening slope. In contrast, within injured mice, we discovered a subset of axotomized layer 5 pyramidal neurons in which the AIS-regional 2opeak was abolished, a functional perturbation associated with diminished excitability, axonal sprouting and distention of the AIS as assessed by staining for ankyrin-G. Our analysis revealed an additional subpopulation of both axotomized and intact layer 5 pyramidal neurons that manifested a melding together of the AIS- and soma-regional 2opeaks, suggesting a more subtle aberration of sodium channel function and/or translocation of the AIS initiation zone closer to the soma. When these experiments were repeated in animals in which cyclophilin-D was knocked out, these effects were ameliorated, suggesting that trauma-induced AIS functional perturbation is associated with mitochondrial calcium dysregulation.