Cellular, Structural and Functional Characterization of Hyperoxia-induced White Matter Injury in the Developing Brain
Ritter, Jonathan L
Diffuse white matter injury (DWMI) is frequently associated with impaired neurological development in pre-mature infants. To characterize the cellular, structural and functional basis of hyperoxia-induced DWMI, the cellular changes in the white matter (WM) were first characterized using mice exposed to 48 hours of 80% oxygen from postnatal day 6 (P6) to postnatal day 8 (P8). Myelin basic protein (MBP) expression and CC1+ oligodendroglia decreased following hyperoxia at P8, but returned to control levels by P15. Hyperoxia caused increased apoptosis and decreased proliferation of oligodendrocyte progenitor cells (OPCs), which was followed by the restoration of the NG2+ cell population and increased oligodendrogenesis in the WM. Hyperoxia, did not affect survival or proliferation of astrocytes in vivo, but modified glial fibrillary acidic protein (GFAP) and glutamate-aspartate transporter (GLAST) expression. The rate of 3H-D-aspartic acid uptake in WM tissue was also diminished at P8 and P12. In addition, cultured astrocytes exposed to hyperoxia showed a reduced capacity to protect OPCs against exogenous glutamate.Upon further analysis, the hyperoxia group was discovered to have decreased myelin associated glycoprotein (MAG) and proteolipid protein (PLP) expression and a decrease in the number of MAG+CC1+ oligodendrocytes until P30. Electron microscopy found this group to also have reduced myelin thickness and axon caliber at P30. The change in axon caliber was associated with diminished neurofilament phosphorylation in axons of the developing WM until P15. Altered paranodal organization was also observed in the hyperoxia group throughout WM maturation. Electrophysiological analysis of the corpus callosum (CC) revealed that mice exposed to neonatal hyperoxia exhibited significant decreases in both myelinated (M) and unmyelinated (UM) compound action potential (CAP) maximum amplitude as well as a reduction in the conduction velocity of myelinated axons. Fractional anisotropy (FA) determined with diffusion tensor imaging (DTI) found that hyperoxia caused a decrease in WM diffusivity at P30 and P60.These studies indicate that a hyperoxia-induced disruption of WM development, through a mechanism involving astrocyte dysfunction/altered glutamate homeostasis, leads to significant lasting changes in WM structure and function. Understanding the underlying pathogenesis of WM injury is important in developing interventional strategies to prevent such pathology.
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