Neuroprotective Role of Hyperoxia During the Critical Period of Retinal Development in Normal Mice and Mice with Retinitis Pigmentosa

Abstract

BackgroundThe retina utilizes more oxygen than any other tissue in the body. Photoreceptors located in the retina's outer nuclear layer (ONL) are culled during the “critical period” of eye development when the number of photoreceptors exceeds the supply of oxygen. Retinitis Pigmentosa (RP) is a disease that first affects the rod photoreceptors, causing night blindness and reduced peripheral vision. In mice, RP often starts during the critical period. The objective of this study was to assess the effects of hyperoxia during the critical period on visual function and morphology of the retina in normal mice and mice with RP.MethodThirty five male and female wild‐type (C57BL/6J) mice and 15 mice with an rd1 mutation (C3H/HeJ), which causes a rapidly progressing form of retinitis pigmentosa, were exposed to hyperoxia (75% O₂), hypoxia (12% O₂), and normoxia (21% O₂) from postnatal (P) days 7 to 20. At P26, electroretinography (ERG) was used to assess the visual function of the photoreceptors (A‐wave) and the inner retinal cells (B‐wave). At P27, optical coherence tomography (OCT) and histology were used to observe retinal structure and the effects of the different O₂ groups. For histology, eyes were extracted at P10, P12, P16, and P28. Cell death was evaluated using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL).ResultsIn ERGs from C57 mice, both A‐wave and B‐wave amplitudes were significantly lower in the hypoxic condition indicating that hypoxia was detrimental to visual function compared to the normoxic group. OCT data showed that the hyperoxic groups of C57 mice had thicker ONLs compared to the other treatment groups. TUNEL cell counts in the ONL and INL indicated a significant decrease in apoptotic cells during the critical period in the hyperoxic group compared to the hypoxic group. In C3H mice, hyperoxia improved the A and B waves compared to untreated mice.DiscussionThis study suggests that administration of oxygen during the critical period of retinal development reduces the pruning of cells in the retina and increases visual function in both normal mice and mice with an aggressive form of RP. Oxygen treatment during the critical period of retinal development, which occurs from P8 to P16, may slow retinal degeneration in RP. The effects of hyperoxia on the completion of vascular development must be taken into account when considering the use of hyperoxia therapeutically.