This study demonstrates that rat pups exposed to HI at P10 developed a retinopathy. Hypoxia-ischemia induced a functional impairment of the inner retina (i.e., the layers of cells connecting the photoreceptors to the brain) while sparing the photoreceptor function, as demonstrated by a severely attenuated b-wave (i.e., activity of the inner retina) in the presence of a well-preserved a-wave (i.e., activity of the photoreceptors) of the mixed rod-cone ERG responses. Rod- and cone-mediated inner retinal functions were compromised, as was demonstrated by the attenuated rod-mediated response (rod V
max) and photopic b-wave. The histology of these eyes confirmed that the RPE and the photoreceptor layers (i.e., the OS, IS, and ONL) were intact, compared to the significantly damaged inner retina (i.e., the OPL, INL, IPL, and RGC/FL). We also confirmed the presence of cerebral damage associated with impaired cerebral visual function as demonstrated by the reduced VEP P100 amplitude and injury on the left hemisphere on brain histology. Interestingly, however, the severity of retinal and cerebral injuries did not correlate, suggesting that visual impairments following HI could arise either from retinal injury, cerebral injury, or a combination of both. This is an important finding, since much of the emphasis until now has been placed on the abnormalities in the intracerebral visual pathways to explain the visual deficits in human newborns with neonatal encephalopathy.
3–11 To our knowledge, this is the first demonstration of such risk in a rat model of term neonatal HIE. Previous animal studies have highlighted the risk of the retinopathy following HI, but in younger animals (i.e., at ages that correspond to human preterm infants in whom retina is well known to be susceptible to damages).
18–20 Kiss et al.
18 reported a reduction in the thickness of the ONL and INL as well as ganglion cell loss in 6-week-old rat retinas following 15 minutes of asphyxia at P0. In another study using a similar rat model, 20 minutes of asphyxia at P0 induced abnormal structural changes in the RGC/FL at P60, marked by neurodegeneration, neovascularization, and gliosis.
19 A 2-hour exposure of P1 rats to 5% oxygen resulted in cell death in the INL and ganglion cell layer, Müller cell swelling, and increased permeability of the retinal blood vessels.
36 Of interest, Huang et al.
20 used the Vannucci model at P7 and demonstrated substantial inner retinal damage (with apoptosis) and gliosis accompanied by a reduction in the ERG b-wave amplitude at P14–60, consistent with our findings. However, they did not report a complete destruction of the IPL and RGC/FL as observed in the severe HI group in our study. The discrepancies between different studies may represent a strain difference in retinal susceptibility to HI, as similar strain difference has been reported in the oxygen-induced retinopathy model.
37 Alternatively, the discrepancies may be due to the difference in the age at which HI was induced. The neurodevelopmental stage of a P0 rat is equivalent to that of very preterm infant (24 weeks gestational age), P7 is equivalent to late-preterm (32–36 weeks gestational age), whereas P10 is considered closer to full-term (40 weeks gestational age).
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