Department of Physiology, Northwestern University, Chicago, Illinois 60611, USA.
J Neurosci. 2010 Apr 21;30(16):5544-58. doi: 10.1523/JNEUROSCI.0434-10.2010.
A critical step in improving our understanding of the development of amyotrophic lateral sclerosis (ALS) is to identify the factors contributing to the alterations in the excitability of motoneurons and assess their individual contributions. Here we investigated the early alterations in the passive electrical and morphological properties of neonatal spinal motoneurons that occur by 10 d after birth, long before disease onset. We identified some of the factors contributing to these alterations, and estimated their individual contributions. To achieve this goal, we undertook a computer simulation analysis using realistic morphologies of reconstructed wild-type (WT) and mutant superoxide dismutase-1 (mSOD1) motoneurons. Ion channel parameters of these models were then tuned to match the experimental data on electrical properties obtained from these same motoneurons. We found that the reduced excitability of mSOD1 models was accompanied with decreased specific membrane resistance by approximately 25% and efficacy of synaptic inputs (slow and fast) by 12-22%. Linearity of summation of synaptic currents was similar to WT. We also assessed the contribution of the alteration in dendritic morphology alone to this decreased excitability and found that it reduced the input resistance by 10% and the efficacy of synaptic inputs by 7-15%. Our results were also confirmed in models with dendritic active conductances. Our simulations indicated that the alteration in passive electrical properties of mSOD1 models resulted from concurrent alterations in their morphology and membrane biophysical properties, and consequently altered the motoneuronal dendritic processing of synaptic inputs. These results clarify new aspects of spinal motoneurons malfunction in ALS.
提高我们对肌萎缩侧索硬化症（ALS）发展的理解的关键步骤是确定导致运动神经元兴奋性改变的因素，并评估它们各自的贡献。在这里，我们研究了出生后 10 天内发生的新生儿脊髓运动神经元的被动电和形态特性的早期改变，此时疾病尚未发生。我们确定了导致这些改变的一些因素，并估计了它们各自的贡献。为了实现这一目标，我们使用重建的野生型（WT）和突变超氧化物歧化酶 1（mSOD1）运动神经元的现实形态进行了计算机模拟分析。然后，调整这些模型的离子通道参数以匹配从相同运动神经元获得的电特性的实验数据。我们发现，mSOD1 模型的兴奋性降低伴随着大约 25%的特定膜电阻降低和突触输入（慢和快）的效率降低 12-22%。突触电流的总和线性与 WT 相似。我们还评估了单独改变树突形态对这种兴奋性降低的贡献，发现它将输入电阻降低了 10%，并将突触输入的效率降低了 7-15%。我们的结果在具有树突主动电导的模型中也得到了证实。我们的模拟表明，mSOD1 模型的被动电特性的改变是由于其形态和膜生物物理特性的同时改变，从而改变了运动神经元对突触输入的树突处理。这些结果阐明了 ALS 中脊髓运动神经元功能障碍的新方面。
