Differential involvement of vesicular and glial glutamate transporters around spinal α-motoneurons in the pathogenesis of SOD1G93A mouse model of amyotrophic lateral sclerosis
Differential involvement of vesicular and glial glutamate transporters around spinal α-motoneurons in the pathogenesis of SOD1G93A mouse model of amyotrophic lateral sclerosis
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脊髓 α 运动神经元周围的囊泡和胶质谷氨酸转运蛋白在肌萎缩侧索硬化症 SOD1G93A 小鼠模型发病机制中的差异参与
DOI：
10.1016/j.neuroscience.2017.05.014
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Jinno Shozo
中科院分区：
文献类型：
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作者：
Ohgomori Tomohiro;Yamasaki Ryo;Takeuchi Hideyuki;Kadomatsu Kenji;Kira Jun-ichi;Jinno Shozo
从谷氨酸兴奋毒性理论的角度来看，一些研究表明，通过胶质细胞谷氨酸转运蛋白-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）神经变性的基础。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，在这里，我们阐明了结构改变与谷氨酸稳态失调使用SOD 1G 93 Amice，一个家族性ALS的遗传模型。我们首先检测了SOD 1G 93 Amice腰髓α运动神经元的活力。对索马体积和密度的测量表明，α运动神经元在9周龄时可能是完整的（症状前期），然后索马体积开始缩小（进行期），最后神经元密度在21周龄时下降（终末期）。接下来，我们进行了线轮廓分析，发现GLT-1阳性（GLT-1+）星形胶质细胞突起对α运动神经元的覆盖仅在21周龄时减少，而突触素阳性（SYP+）突触前末梢对α运动神经元的覆盖减少在15周龄时开始。有趣的是，α-运动神经元的VGluT 2+突触前末梢的覆盖率在9周龄时短暂增加，然后在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时间依赖性变化。这些结果表明，VGluT 2和GLT-1可能分别通过异常的谷氨酸稳态在症状前阶段和疾病的终末期差异参与ALS的发病机制。
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 usingSOD1G93Amice, a genetic model of familial ALS. We first examined the viability of α-motoneurons in the lumbar spinal cord ofSOD1G93Amice. Measurement of the soma size and density indicated that α-motoneurons might be intact at 9 weeks of age (presymptomatic stage), then soma shrinkage began at 15 weeks of age (progressive stage), and finally neuronal density declined at 21 weeks 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 21 weeks of age, while the reduction of coverage of α-motoneurons by synaptophysin-positive (SYP+) presynaptic terminals began at 15 weeks of age. Interestingly, the coverage of α-motoneurons by VGluT2+presynaptic terminals was transiently increased at 9 weeks of age, and then gradually decreased towards 21 weeks 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.