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D. M. Wu, J. Zheng, D. G. Puro, N. L. Hawes, B. Chang, J. R. Heckenlively, D. N. Zacks; Apoptosis in the nm3342 Mouse Model of Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4494.
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Recent work in a surgically-induced retinal detachment model has shown that photoreceptor apoptosis can be reduced by the endogenously produced neuoroprotective cytokine Interleukin-6 (IL-6). We hypothesize that the loss of endogenous IL-6 may contribute to photoreceptor loss in nm3342, a mouse mutant that develops focal areas of retinal degeneration.
nm3342 mice were examined at 21, 25, 39, 54, 67, 90, 136, 172, 255, and 411 days. Terminal deoxynucleotidyl transferase dTUP nick end labeling (TUNEL) was used to detect apoptosis. Outer and inner nuclear layer (ONL/INL) cell counts were perormed. Antibody staining was used to localize IL-6 expression. Perforated patch-clamp recordings were made from freshly isolated retinal microvessels.
Mice developed white retinal patches as early as 54 days, typically in superotemporal retina. The patches progressively expanded in size and number. These correlated with disruption of the neurosensory retina/retinal pigment epithelial interface. There was a significant time-dependent photoreceptor loss in these regions; the ONL to INL ratio decreased from 1.27 at 25 days to 0.78 at 411 days. Antibody staining showed a decline in IL-6 with age in nm3342 mice. A subset of nm3342 mice show vascular leakage on fluorescein angiography, so we used perforated patch-clamp recordings to monitor the retinal microvessels. nm3342 mice had significantly lower membrane resistance (0-200 megohms) compared to control mice (200-600 meghoms).
The nm3342 mouse develops patchy retinal degeneration with age, apoptotic photoreceptor death, and a decrease in endogenous IL-6 neuroprotectant. Apoptotic cell death and decreased endogenous IL-6 levels are also seen in surgically induced retinal detachment, suggesting a common injury pathway. Further work is needed to understand the root cause of retinal degeneration in the nm3342 mice. The basal ionic conductance in microvessels from nm3342 mice is significantly greater than that in control mice, suggesting a role for microvascular dysfunction in the degeneration of nm3342 mouse retinas.
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