NMDA receptors are expressed in developing oligodendrocyte processes and mediate injury
NMDA receptors are expressed in developing oligodendrocyte processes and mediate injury
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DOI：
10.1038/nature04301
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发表时间：
2005-12-22
期刊：
影响因子：
64.8
通讯作者：
Fern, R
中科院分区：
文献类型：
--
作者：
Salter, MG;Fern, R
对负责髓鞘形成的少突胶质细胞过程的损伤涉及许多形式的脑疾病（1-4）。在这里，我们显示NMDA（N-甲基-D-天冬氨酸）受体亚单位表达的少突胶质细胞的过程中，和NMDA受体亚单位信使RNA的存在下，在孤立的白色的问题。NR 1、NR 2A、NR 2B、NR 2C、NR 2D和NR 3A亚基在细胞突起中呈聚集性表达，但NR 3B亚基不表达。在模拟缺血期间，NMDA受体激活导致在少突胶质细胞中特异性表达绿色荧光蛋白（GFP）的小鼠（CNP-GFP小鼠）的白色物质中的少突胶质细胞过程的快速Ca 2+依赖性脱离和崩解。这种效应发生在对应于髓鞘形成的开始和结束的小鼠年龄。NR 1主要分布在少突胶质细胞突起中，而AMPA（α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid）/kainate受体主要分布在胞体中。与这一观察结果一致，通过阻断AMPA/红藻氨酸受体来防止对胞体的损伤，并且防止对少突胶质细胞过程的损伤需要阻断NMDA受体。NMDA受体在少突胶质细胞过程中的存在解释了为什么以前的研究集中在胞体没有检测到NMDA受体在少突胶质细胞损伤中的作用。这些NMDA受体对急性损伤具有高度敏感性，并代表了各种脑疾病药物开发的重要新靶点。
Injury to oligodendrocyte processes, the structures responsible for myelination, is implicated in many forms of brain disorder(1-4). Here we show NMDA (N-methyl-D-aspartate) receptor subunit expression on oligodendrocyte processes, and the presence of NMDA receptor subunit messenger RNA in isolated white matter. NR1, NR2A, NR2B, NR2C, NR2D and NR3A subunits showed clustered expression in cell processes, but NR3B was absent. During modelled ischaemia, NMDA receptor activation resulted in rapid Ca2+-dependent detachment and disintegration of oligodendroglial processes in the white matter of mice expressing green fluorescent protein (GFP) specifically in oligodendrocytes (CNP-GFP mice). This effect occurred at mouse ages corresponding to both the initiation and the conclusion of myelination. NR1 subunits were found mainly in oligodendrocyte processes, whereas AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)/kainate receptor subunits were mainly found in the somata. Consistent with this observation, injury to the somata was prevented by blocking AMPA/kainate receptors, and preventing injury to oligodendroglial processes required the blocking of NMDA receptors. The presence of NMDA receptors in oligodendrocyte processes explains why previous studies that have focused on the somata have not detected a role for NMDA receptors in oligodendrocyte injury. These NMDA receptors bestow a high sensitivity to acute injury and represent an important new target for drug development in a variety of brain disorders.