Towards improved animal models of neonatal white matter injury associated with cerebral palsy

Abstract

Newborn neurological injuries are the leading cause of intellectual and motor disabilities that are associated with cerebral palsy. Cerebral white matter injury is a common feature in hypoxic-ischemic encephalopathy (HIE), which affects full-term infants, and in periventricular leukomalacia (PVL), which affects preterm infants. This article discusses recent efforts to model neonatal white matter injury using mammalian systems. We emphasize that a comprehensive understanding of oligodendrocyte development and physiology is crucial for obtaining new insights into the pathobiology of HIE and PVL as well as for the generation of more sophisticated and faithful animal models.

Fig. 1.

Common types of injury associated with development of CP in ELBW and term infants. (A,B) Illustration of brain injuries commonly affecting ELBW infants. (A) Key characteristics of intraventricular hemorrhage, which results from germinal matrix hemorrhage into the ventricles, sometimes extending into the brain parenchyma, are shown. Additionally, there is a high incidence of PVL (a type of WMI), which can result in a cystic necrosis of white matter tracts and/or diffuse gliosis. (B) Long-term sequelae of brain injury in ELBW infants are shown, including hypomyelination resulting from failure of lesion repair, as well as ventriculomegaly, which represents an ex-vacuo change resulting from significant loss of brain parenchyma. (C,D) Common brain injuries in full-term infants. (C) Neonatal stroke in which a focal region of cortex is affected. (D) HIE results in global HI injury to the brain, more specifically to neurons of the cortical plate and basal ganglia, as well as white matter tracts.

Fig. 2.

Markers of oligodendrocyte lineage specification and maturation. The schematic shows oligodendrocyte lineage progression from OPCs to preOLs and then to myelinating oligodendrocytes. In the past decade, various markers have been identified that show lineage- and stage-specific expression (indicated by colored gradients). The markers PDGFRα, Olig2, Nkx2.2, Sox10, NG2 and Olig1 (nuclear) (indicated in orange) are characteristic of OPCs. O4 and O1 [also known as galactocebroside (GalC)] (indicated in red) mark intermediate preOLs, whereas APC (also known as CC1), myelin basic protein (MBP), myelin proteolipid protein (PLP) and Olig1 (cytoplasmic) (indicated in blue) are typical of mature myelinating oligodendrocytes. Several laboratories studying MS and PVL have reported abnormal oligodendrocyte differentiation in these disorders, suggesting that these abnormalities are associated with a failure to repair demyelinated lesions.

Fig. 3.

Oligodendrocytes are generated in multiple waves and in various locations of the CNS. Results from the Richardson laboratory and others have shown that, in mice, oligodendrocytes of the forebrain are initially specified in ventral regions, such as the medial ganglionic eminence (MGE; corresponding to region 1 in the figure), a ventral domain of embryonic proliferative precursor cells, from which the oligodendrocytes migrate to more dorsal areas of the brain (Kessaris et al., 2006). At subsequent developmental stages, later waves of oligodendrocytes are produced in successively more dorsal regions, such as the lateral ganglionic eminence (LGE, corresponding to region 2) in late embryonic development and the cerebral cortex (CX, corresponding to region 3) in the early postnatal period. The first three waves of oligodendrocyte production are shown. In addition, NG2-positive precursor cells continue to cycle in the adult brain and are thought to contribute to oligodendrocyte turnover, as well as the response to injury (not shown). It is unclear whether oligodendrocytes from different regions of the brain have cell-intrinsic differences in their ability to repair myelin, or in their vulnerability to HI or other toxic insults.