PDF(Pubmed)
Abstract：
In a variety of neurons, action potentials (APs) initiate at the proximal axon, within a region called the axon initial segment (AIS), which has a high density of voltage-gated sodium channels (NaVs) on its membrane. In pyramidal neurons, the proximal AIS has been reported to exhibit a higher proportion of NaVs with gating properties that are \"right-shifted\" to more depolarized voltages, compared to the distal AIS. Further, recent experiments have revealed that as neurons develop, the spatial distribution of NaV subtypes along the AIS can change substantially, suggesting that neurons tune their excitability by modifying said distribution. When neurons are stimulated axonally, computational modelling has shown that this spatial separation of gating properties in the AIS enhances the backpropagation of APs into the dendrites. In contrast, in the more natural scenario of somatic stimulation, our simulations show that the same distribution can impede backpropagation, suggesting that the choice of orthodromic versus antidromic stimulation can bias or even invert experimental findings regarding the role of NaV subtypes in the AIS. We implemented a range of hypothetical NaV distributions in the AIS of three multicompartmental pyramidal cell models and investigated the precise kinetic mechanisms underlying such effects, as the spatial distribution of NaV subtypes is varied. With axonal stimulation, proximal NaV availability dominates, such that concentrating right-shifted NaVs in the proximal AIS promotes backpropagation. However, with somatic stimulation, the models are insensitive to availability kinetics. Instead, the higher activation threshold of right-shifted NaVs in the AIS impedes backpropagation. Therefore, recently observed developmental changes to the spatial separation and relative proportions of NaV1.2 and NaV1.6 in the AIS differentially impact activation and availability. The observed effects on backpropagation, and potentially learning via its putative role in synaptic plasticity (e.g. through spike-timing-dependent plasticity), are opposite for orthodromic versus antidromic stimulation, which should inform hypotheses about the impact of the developmentally regulated subcellular localization of these NaV subtypes.
摘要：
在各种神经元中，动作电位（AP）在近端轴突启动，在称为轴突初始部分(AIS)的区域内，其膜上具有高密度的电压门控钠通道（Navs）。在锥体神经元中，据报道，近端AIS表现出更高比例的具有“右移”到更多去极化电压的门控特性的Navs，与远端AIS相比。Further,最近的实验表明，随着神经元的发育，NaV亚型沿AIS的空间分布可以发生实质性变化，这表明神经元通过修改所述分布来调节其兴奋性。当神经元受到轴突刺激时，计算模型表明，AIS中门控特性的这种空间分离增强了AP向树突的反向传播。相比之下,在更自然的躯体刺激中，我们的模拟表明，相同的分布会阻碍反向传播，这表明，选择直行刺激与反行刺激可能会使有关NaV亚型在AIS中的作用的实验结果产生偏差甚至颠倒。我们在三个多室锥体细胞模型的AIS中实施了一系列假设的NaV分布，并研究了这种影响的精确动力学机制。随着NaV亚型的空间分布变化。用轴突刺激,近端NaV可用性占主导地位，这样在近端AIS中集中右移的Navs会促进反向传播。然而,通过躯体刺激，这些模型对可用性动力学不敏感。相反，AIS中右移位的NaV的较高激活阈值阻碍了反向传播。因此,最近观察到的AIS中NaV1.2和NaV1.6的空间分离和相对比例的发育变化差异影响激活和可用性。观察到的对反向传播的影响，并通过其在突触可塑性中的假定作用（例如，通过尖峰时间依赖性可塑性）进行潜在学习，正行刺激与反行刺激相反，这应该提供有关这些NaV亚型的发育调节的亚细胞定位的影响的假设。
