Deletion of astrocyte connexins 43 and 30 leads to a dysmyelinating phenotype and hippocampal CA1 vacuolation.
Deletion of astrocyte connexins 43 and 30 leads to a dysmyelinating phenotype and hippocampal CA1 vacuolation.
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DOI：
10.1523/jneurosci.0341-09.2009
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发表时间：
2009-06-17
期刊：
影响因子：
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通讯作者：
Brosnan CF
中科院分区：
文献类型：
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作者：
Lutz SE;Zhao Y;Gulinello M;Lee SC;Raine CS;Brosnan CF
星形胶质细胞通过由连接蛋白43（Gja 1）和Cx30（Gjb 6）组成的间隙连接（GJ）偶联，所述间隙连接促进细胞间的离子交换。星形胶质细胞连接蛋白还与少突胶质细胞胞体和片层形成异型GJ。少突胶质细胞间隙连接的缺失导致少突胶质细胞和髓鞘病理学。然而，星形胶质细胞GJ的丧失是否影响少突胶质细胞和髓鞘尚不清楚。为了解决这个问题，使用蛋白质印迹、免疫组织化学、电子显微镜和功能测定研究了具有星形胶质细胞靶向的Cx43缺失和Cx30全局缺失（双敲除，dKO）的小鼠。从出生后第23天开始，一直持续到老年，我们发现广泛的病理学白色物质束包括空泡化少突胶质细胞和髓鞘内水肿。相反，灰质病理仅限于海马CA1区，由水肿的星形胶质细胞组成。在海马中的突触密度或总NeuN+细胞或胼胝体中的olig2+细胞中未观察到差异。然而，在dKO小鼠中，检测到较少的CC1阳性成熟少突胶质细胞，蛋白质印迹法表明髓鞘碱性蛋白减少。在表达Cx43或Cx30的单个等位基因的小鼠中未观察到病理学。当与单一连接蛋白敲除相比时，dKO小鼠在感觉运动（旋转杆、平衡木测定）和空间记忆任务（物体识别测定）中受损。我们的结论是，星形胶质细胞GJ的损失可导致白色物质病理，具有功能性后果。
Astrocytes are coupled via gap junctions (GJ) comprised of connexin 43 (Gja1) and Cx30 (Gjb6) that facilitate intercellular exchange of ions. Astrocyte connexins also form heterotypic GJ with oligodendrocytic somata and lamellae. Loss of oligodendrocyte gap junctions results in oligodendrocyte and myelin pathology. However, whether loss of astrocyte GJ affects oligodendrocytes and myelin is not known. To address this question, mice with astrocyte-targeted deletion of Cx43 and global loss of Cx30 (double knock-out, dKO) were studied using western blotting, immunohistochemistry, electron microscopy, and functional assays. Commencing around post-natal day 23 and persisting into old age, we found widespread pathology of white matter tracts comprising vacuolated oligodendrocytes and intramyelinic edema. In contrast, gray matter pathology was restricted to the CA1 region of the hippocampus, and consisted of edematous astrocytes. No differences were observed in synaptic density or total NeuN+ cells in the hippocampus, or olig2+ cells in the corpus callosum. However, in dKO mice, fewer CC1-positive mature oligodendrocytes were detected, and western blotting indicated reduced myelin basic protein. Pathology was not noted in mice expressing a single allele of either Cx43 or Cx30. When compared with single connexin knock-outs, dKO mice were impaired in sensorimotor (rotarod, balance beam assays) and spatial memory tasks (object recognition assays). We conclude that loss of astrocytic GJ can result in white matter pathology that has functional consequences.