Developmental window of vulnerability to white matter injury driven by sublethal intermittent hypoxemia

BACKGROUND: In the developing brain, the death of immature oligodendrocytes (OLs) has been proposed to explain a developmental window for vulnerability to white matter injury (WMI). However, in neonatal mice, chronic sub-lethal intermittent hypoxia (IH) recapitulates the phenotype of diffuse WMI without affecting cellular viability. This work determines whether, in neonatal mice, a developmental window of WMI vulnerability exists in the absence of OLs lineage cellular death. METHODS: Neonatal mice were exposed to cell-nonlethal early or late IH stress. The presence or absence of WMI phenotype in their adulthood was defined by the extent of sensorimotor deficit and diffuse cerebral hypomyelination. A separate cohort of mice was examined for markers of cellular degeneration and OLs maturation. RESULTS: Compared to normoxic littermates, only mice exposed to early IH-stress demonstrated arrested OLs maturation, diffuse cerebral hypomyelination and sensorimotor deficit. No cellular death associated with IH was detected. CONCLUSION: Neonatal sub-lethal IH recapitulates the phenotype of diffuse WMI only when IH-stress coincides with the developmental stage of primary white matter myelination. This signifies a contribution of cell-nonlethal mechanisms in defining the developmental window of vulnerability to diffuse WMI.