Department of Neonatology, Children's Hospital of Fudan University, Shanghai, China; Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China.
Department of Neonatology, Children's Hospital of Fudan University, Shanghai, China.
Exp Neurol. 2015 Jul;269:213-23. doi: 10.1016/j.expneurol.2015.03.026. Epub 2015 Apr 8.
Hypomyelination is the major cause of neurodevelopmental deficits that are associated with perinatal white matter injury. Chondroitin sulfate proteoglycans (CSPGs) are known to exert inhibitory effects on the migration and differentiation of oligodendrocytes (OLs). However, few studies describe the roles of CSPGs in myelination by OLs and the cognitive dysfunction that follows perinatal white matter injury. Here, we examined the alterations in the expression of CSPGs and their functional impact on the maturation of OLs and myelination in a neonatal rat model of hypoxic-ischemic (HI) brain injury. Three-day-old Sprague-Dawley rats underwent a right common carotid artery ligation and were exposed to hypoxia (6% oxygen for 2.5h). Rats were given chondroitinase ABC (cABC) via an intracerebroventricular injection to digest CSPGs. Animals were sacrificed at 7, 14, 28 and 56days after HI injury and the accompanying surgical procedure. We found that the expression of CSPGs was significantly up-regulated in the cortical regions surrounding the white matter after HI injury. cABC successfully degraded CSPGs in the rats that received cABC. Immunostaining showed decreased expression of the pre-oligodendrocyte marker O4 in the cingulum, external capsule and corpus callosum in HI+cABC rats compared to HI rats. However HI+cABC rats exhibited greater maturation of OLs than did HI rats, with increased expression of O1 and myelin basic protein in the white matter. Furthermore, using electron microscopy, we demonstrated that myelin formation was enhanced in HI+cABC rats, which had an increased number of myelinated axons and decreased G-ratios of myelin compared to HI rats. Finally, HI+cABC rats performed better in the Morris water maze task than HI rats, which indicates an improvement in cognitive ability. Our results suggest that CSPGs inhibit both the maturation of OLs and the process of myelination after neonatal HI brain injury. The data also raise the possibility that modifying CSPGs may repair this type of lesion associated with demyelination.
Hypomyelination 是与围产期白质损伤相关的神经发育缺陷的主要原因。软骨素硫酸盐蛋白聚糖（CSPGs）已知对少突胶质细胞（OLs）的迁移和分化具有抑制作用。然而，很少有研究描述 CSPGs 在 OL 髓鞘形成中的作用以及围产期白质损伤后的认知功能障碍。在这里，我们在新生大鼠缺氧缺血（HI）脑损伤模型中检查了 CSPGs 的表达变化及其对 OL 成熟和髓鞘形成的功能影响。3 天大的 Sprague-Dawley 大鼠接受右侧颈总动脉结扎，并暴露于缺氧（2.5h 6%氧气）下。通过脑室内注射给予软骨素酶 ABC（cABC）以消化 CSPGs。在 HI 损伤和伴随的手术程序后 7、14、28 和 56 天处死动物。我们发现 HI 损伤后白质周围皮质区 CSPGs 的表达显著上调。cABC 成功降解了接受 cABC 的大鼠中的 CSPGs。免疫染色显示，与 HI 大鼠相比，HI+cABC 大鼠的扣带束、外囊和胼胝体中的前少突胶质细胞标志物 O4 表达减少。然而，与 HI 大鼠相比，HI+cABC 大鼠的 OL 成熟度更高，白质中 O1 和髓鞘碱性蛋白的表达增加。此外，通过电子显微镜，我们证明 HI+cABC 大鼠的髓鞘形成增强，与 HI 大鼠相比，髓鞘化轴突数量增加，髓鞘 G-比降低。最后，HI+cABC 大鼠在 Morris 水迷宫任务中的表现优于 HI 大鼠，这表明认知能力有所提高。我们的结果表明，CSPGs 抑制新生 HI 脑损伤后 OL 的成熟和髓鞘形成过程。这些数据还提出了一种可能性，即修饰 CSPGs 可能修复与脱髓鞘相关的这种类型的病变。
