Cellular changes underlying hyperoxia-induced delay of white matter development.

Impaired neurological development in premature infants frequently arises from periventricular white matter injury (PWMI), a condition associated with myelination abnormalities. Recently, exposure to hyperoxia was reported to disrupt myelin formation in neonatal rats. To identify the causes of hyperoxia-induced PWMI, we characterized cellular changes in the white matter (WM) using neonatal wild-type 2-3-cyclic nucleotide 3-phosphodiesterase-enhanced green fluorescent protein (EGFP) and glial fibrillary acidic protein (GFAP)-EGFP transgenic mice exposed to 48 h of 80% oxygen from postnatal day 6 (P6) to P8. Myelin basic protein expression and CC1(+) oligodendroglia decreased after hyperoxia at P8, but returned to control levels during recovery between P12 and P15. At P8, hyperoxia caused apoptosis of NG2(+)O4(-) progenitor cells and reduced NG2(+) cell proliferation. This was followed by restoration of the NG2(+) cell population and increased oligodendrogenesis in the WM after recovery. Despite apparent cellular recovery, diffusion tensor imaging revealed WM deficiencies at P30 and P60. Hyperoxia did not affect survival or proliferation of astrocytes in vivo, but modified GFAP and glutamate-aspartate transporter expression. The rate of [(3)H]-d-aspartic acid uptake in WM tissue was also decreased at P8 and P12. Furthermore, cultured astrocytes exposed to hyperoxia showed a reduced capacity to protect oligodendrocyte progenitor cells against the toxic effects of exogenous glutamate. This effect was prevented by 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide treatment. Our analysis reveals a role for altered glutamate homeostasis in hyperoxia-induced WM damage. Understanding the cellular dynamics and underlying mechanisms involved in hyperoxia-induced PWMI will allow for future targeted therapeutic intervention.