Department of Neuroscience, Cell Biology, and Physiology, Boonshoft School of Medicine and College of Science and Mathematics, Wright State University, Dayton, OH, 45435, USA.
Department of Biomedical, Industrial, and Human Factors Engineering, College of Engineering and Computer Science, Wright State University, Dayton, OH 45435, USA.
J Physiol. 2018 May 1;596(9):1723-1745. doi: 10.1113/JP275498. Epub 2018 Mar 26.
Motoneuron soma size is a largely plastic property that is altered during amyotrophic lateral sclerosis (ALS) progression. We report evidence of systematic spinal motoneuron soma size plasticity in mutant SOD1-G93A mice at various disease stages and across sexes, spinal regions and motoneuron types. We show that disease-vulnerable motoneurons exhibit early increased soma sizes. We show via computer simulations that the measured changes in soma size have a profound impact on the excitability of disease-vulnerable motoneurons. This study reveals a novel form of plasticity in ALS and suggests a potential target for altering motoneuron function and survival.
α-Motoneuron soma size is correlated with the cell's excitability and function, and has been posited as a plastic property that changes during cellular maturation, injury and disease. This study examined whether α-motoneuron somas change in size over disease progression in the G93A mouse model of amyotrophic lateral sclerosis (ALS), a disease characterized by progressive motoneuron death. We used 2D- and 3D-morphometric analysis of motoneuron size and measures of cell density at four key disease stages: neonatal (P10 - with earliest known disease changes); young adult (P30 - presymptomatic with early motoneuron death); symptom onset (P90 - with death of 70-80% of motoneurons); and end-stage (P120+ - with full paralysis of hindlimbs). We additionally examined differences in lumbar vs. sacral vs. cervical motoneurons; in motoneurons from male vs. female mice; and in fast vs. slow motoneurons. We present the first evidence of plastic changes in the soma size of spinal α-motoneurons occurring throughout different stages of ALS with profound effects on motoneuron excitability. Somatic changes are time dependent and are characterized by early-stage enlargement (P10 and P30); no change around symptom onset; and shrinkage at end-stage. A key finding in the study indicates that disease-vulnerable motoneurons exhibit increased soma sizes (P10 and P30). This pattern was confirmed across spinal cord regions, genders and motoneuron types. This extends the theory of motoneuron size-based vulnerability in ALS: not only are larger motoneurons more vulnerable to death in ALS, but are also enlarged further in the disease. Such information is valuable for identifying ALS pathogenesis mechanisms.
运动神经元胞体大小是一个高度可塑的特性，在肌萎缩侧索硬化症（ALS）进展过程中会发生改变。我们报告了在各种疾病阶段和性别、脊髓区域和运动神经元类型的突变 SOD1-G93A 小鼠中存在系统性脊髓运动神经元胞体大小可塑性的证据。我们表明，易患病的运动神经元表现出早期增大的胞体大小。通过计算机模拟，我们表明胞体大小的测量变化对易患病运动神经元的兴奋性有深远影响。这项研究揭示了 ALS 中的一种新形式的可塑性，并为改变运动神经元功能和存活提供了一个潜在的目标。
α-运动神经元胞体大小与细胞的兴奋性和功能相关，并被认为是一种在细胞成熟、损伤和疾病过程中发生变化的可塑特性。本研究检查了在肌萎缩侧索硬化症（ALS）的 G93A 小鼠模型中，α-运动神经元胞体是否会随着疾病的进展而改变大小，该疾病的特征是运动神经元进行性死亡。我们使用 2D 和 3D 形态计量分析了运动神经元的大小和细胞密度的测量值，在四个关键疾病阶段：新生儿（P10-最早出现已知的疾病变化）；年轻成年（P30-出现早期运动神经元死亡的无症状期）；症状发作（P90-运动神经元死亡 70-80%）；和终末期（P120+ -后肢完全瘫痪）。我们还检查了腰椎与骶骨与颈段运动神经元的差异；雄性与雌性小鼠的运动神经元的差异；以及快肌与慢肌运动神经元的差异。我们首次提出了在 ALS 的不同阶段，脊髓α-运动神经元的胞体大小发生可塑性变化的证据，对运动神经元的兴奋性有深远影响。躯体变化是时间依赖性的，其特征是早期增大（P10 和 P30）；症状发作时无变化；终末期缩小。该研究的一个关键发现表明，易患病的运动神经元表现出增大的胞体大小（P10 和 P30）。这种模式在脊髓区域、性别和运动神经元类型中得到了证实。这扩展了基于运动神经元大小的 ALS 易感性理论：不仅较大的运动神经元在 ALS 中更容易死亡，而且在疾病中进一步增大。这些信息对于确定 ALS 发病机制非常有价值。
