Ohgomori Tomohiro, Yamasaki Ryo, Takeuchi Hideyuki, Kadomatsu Kenji, Kira Jun-Ichi, Jinno Shozo
Department of Anatomy and Neuroscience, Graduate School of Medical Science, Kyushu University, Fukuoka 812-8582, Japan.
Department of Neurology, Neurological Institute, Graduate School of Medical Science, Kyushu University, Fukuoka 812-8582, Japan.
Neuroscience. 2017 Jul 25;356:114-124. doi: 10.1016/j.neuroscience.2017.05.014. Epub 2017 May 17.
From a view point of the glutamate excitotoxicity theory, several studies have suggested that abnormal glutamate homeostasis via dysfunction of glial glutamate transporter-1 (GLT-1) may underlie neurodegeneration in amyotrophic lateral sclerosis (ALS). However, the detailed role of GLT-1 in the pathogenies of ALS remains controversial. To assess this issue, here we elucidated structural alterations associated with dysregulation of glutamate homeostasis using SOD1 mice, a genetic model of familial ALS. We first examined the viability of α-motoneurons in the lumbar spinal cord of SOD1 mice. Measurement of the soma size and density indicated that α-motoneurons might be intact at 9weeks of age (presymptomatic stage), then soma shrinkage began at 15weeks of age (progressive stage), and finally neuronal density declined at 21weeks of age (end stage). Next, we carried out the line profile analysis, and found that the coverage of α-motoneurons by GLT-1-positive (GLT-1) astrocytic processes was decreased only at 21weeks of age, while the reduction of coverage of α-motoneurons by synaptophysin-positive (SYP) presynaptic terminals began at 15weeks of age. Interestingly, the coverage of α-motoneurons by VGluT2 presynaptic terminals was transiently increased at 9weeks of age, and then gradually decreased towards 21weeks of age. On the other hand, there were no time-dependent alterations in the coverage of α-motoneurons by GABAergic presynaptic terminals. These findings suggest that VGluT2 and GLT-1 may be differentially involved in the pathogenesis of ALS via abnormal glutamate homeostasis at the presymptomatic stage and end stage of disease, respectively.
从谷氨酸兴奋性毒性理论的角度来看，多项研究表明，通过胶质谷氨酸转运体-1（GLT-1）功能障碍导致的谷氨酸稳态异常可能是肌萎缩侧索硬化症（ALS）神经退行性变的基础。然而，GLT-1在ALS发病机制中的具体作用仍存在争议。为了评估这个问题，我们在这里使用家族性ALS的遗传模型SOD1小鼠，阐明了与谷氨酸稳态失调相关的结构改变。我们首先检测了SOD1小鼠腰脊髓中α运动神经元的活力。对胞体大小和密度的测量表明，α运动神经元在9周龄（症状前期）时可能完好无损，然后在15周龄（进展期）时开始出现胞体萎缩，最终在21周龄（终末期）时神经元密度下降。接下来，我们进行了线轮廓分析，发现仅在21周龄时，GLT-1阳性（GLT-1）星形胶质细胞突起对α运动神经元的覆盖减少，而突触素阳性（SYP）突触前终末对α运动神经元的覆盖减少在15周龄时就已开始。有趣的是，VGluT2突触前终末对α运动神经元的覆盖在9周龄时短暂增加，然后在接近21周龄时逐渐减少。另一方面，GABA能突触前终末对α运动神经元的覆盖没有随时间的变化。这些发现表明，VGluT2和GLT-1可能分别通过疾病症状前期和终末期的谷氨酸稳态异常，以不同方式参与ALS的发病机制。
