title: Chondroitin sulfate proteoglycans impede myelination by oligodendrocytes after perinatal white matter injury.
abstract: 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.
authors: Department of Neonatology, Children's Hospital of Fudan University, Shanghai, China; Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China.
authors: Ying-Ping
authors: YP
authors: Deng
authors: Department of Neonatology, Children's Hospital of Fudan University, Shanghai, China.
authors: Yi
authors: Y
authors: Sun
authors: Department of Neonatology, Children's Hospital of Fudan University, Shanghai, China.
authors: Lan
authors: L
authors: Hu
authors: Department of Neonatology, Children's Hospital of Fudan University, Shanghai, China.
authors: Zhi-Hua
authors: ZH
authors: Li
authors: Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China.
authors: Quan-Mei
authors: QM
authors: Xu
authors: School of Public Health, Fudan University, Shanghai, China.
authors: Yi-Ling
authors: YL
authors: Pei
authors: Department of Neonatology, Children's Hospital of Fudan University, Shanghai, China; Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China.
authors: Zhi-Heng
authors: ZH
authors: Huang
authors: Institute of Brain Science, Fudan University, Shanghai, China.
authors: Zhen-Gang
authors: ZG
authors: Yang
authors: Department of Neonatology, Children's Hospital of Fudan University, Shanghai, China; Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China. Electronic address: chen6010@163.com.
authors: Chao
authors: C
authors: Chen
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000502:physiology*; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism*; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism / Q000473:pathology; D004676:Myelin Basic Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism*; D009836:Oligodendroglia / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D066127:White Matter / Q000293:injuries / Q000378:metabolism*
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; D004676:Myelin Basic Protein
keywords: Chondroitin sulfate proteoglycan; Cognitive dysfunction; Hypomyelination; Hypoxia–ischemia; Newborn; Rat