B.R.A.I.N. Laboratory for Neurogenesis and Repair, Department of Life Sciences, University of Trieste, Trieste, Italy.
Department of Biomedical and Biotechnological Sciences, Physiology Section, University of Catania, Catania, Italy.
J Comp Neurol. 2020 Feb 1;528(2):231-243. doi: 10.1002/cne.24751. Epub 2019 Aug 7.
Plastic changes have been reported in the SOD1-G93A mouse model of amyotrophic lateral sclerosis, a disorder characterized by progressive motoneuronal loss; however, whether these changes related with the onset and development of motor impairments is still unclear. Here, the functional and anatomical changes taking place in SOD1-G93A mice and their time course were investigated during ongoing motoneuronal degeneration. Starting from about 4 postnatal weeks, SOD1-G93A and wild-type (WT) mice were evaluated in the rotarod test, to be sacrificed at about 12-13 or 19 weeks of age, and their lumbar spinal cords were processed for histo- and immunohistochemistry. Compared to age-matched WT controls, 12 weeks-old SOD1-G93A mice exhibited relatively mild or no motor impairments in the rotarod test, in spite of a dramatic (≈60%, as estimated by stereology) loss of choline acetyl-transferase (ChAT)-immunoreactive motoneurons which remained virtually unchanged in SOD1-G93A mice surviving up to 19 weeks. Notably, the functional sparing in SOD1-G93A mice at 12 weeks was paralleled by a marked ≈50% increase in motoneuron volume and a near-normal density of acetylcholinesterase-positive process arborization, which was significantly increased when analyzed as ratio to the decreased number of ChAT-positive motoneurons. By contrast, at 19 weeks, when motor deficits had become dramatically evident, both measures were found reverted to about 50-60% of control values. Thus, at specific stages during the progression of the disease, robust compensatory events take place in surviving motoneurons of SOD1-G93A mice, which sustain motor performance, and whose full understanding may highlight a valuable therapeutic opportunity window.
在肌萎缩侧索硬化症（ALS）的 SOD1-G93A 小鼠模型中已经报道了可塑性变化，该疾病的特征是进行性运动神经元丧失；然而，这些变化是否与运动功能障碍的发生和发展有关仍不清楚。在这里，研究了在持续运动神经元退化过程中 SOD1-G93A 小鼠发生的功能和解剖变化及其时间过程。从大约 4 周龄开始，对 SOD1-G93A 和野生型（WT）小鼠进行了旋转棒试验评估，然后在大约 12-13 或 19 周龄时处死，并对其腰脊髓进行了组织学和免疫组织化学处理。与年龄匹配的 WT 对照组相比，12 周龄的 SOD1-G93A 小鼠在旋转棒试验中表现出相对较轻或没有运动功能障碍，尽管胆碱乙酰转移酶（ChAT）免疫反应性运动神经元的数量急剧减少（通过体视学法估计约为 60%），但在存活至 19 周龄的 SOD1-G93A 小鼠中几乎没有变化。值得注意的是，SOD1-G93A 小鼠在 12 周龄时的功能保留与运动神经元体积增加约 50%相平行，并且乙酰胆碱酯酶阳性过程分支的密度接近正常，当按减少的 ChAT 阳性运动神经元的数量进行分析时，其密度显著增加。相比之下，在 19 周龄时，当运动缺陷变得非常明显时，这两个指标都恢复到约 50-60%的对照值。因此，在疾病进展的特定阶段，SOD1-G93A 小鼠存活的运动神经元中会发生强大的代偿事件，从而维持运动表现，对其充分理解可能突出了一个有价值的治疗机会窗口。
