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Steven Fliesler, Christopher Goulah, William Ferrell, Robert Marc, Bryan Jones; Retinal Remodeling in a Rat Model of the Smith-Lemli-Opitz Syndrome. Invest. Ophthalmol. Vis. Sci. 2013;54(15):711.
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Smith-Lemli-Opitz syndrome (SLOS) is a developmental disorder involving defective cholesterol biosynthesis. Prior studies using a rat model of SLOS have documented progressive retinal dysfunction and degeneration, apparently involving caspase-3-independent cell death of photoreceptors. Retinal remodeling has been documented in human retinal degenerations and a myriad of animal models of retinal disease (Jpn J Ophthalmol. 56(4):289, 2012). Here, we examined retinal degeneration and remodeling in the SLOS rat model vs. age-matched control rats.
A pharmacologically-induced rat model of SLOS was generated by treating Sprague-Dawley rats with AY9944 (Arch. Ophthalmol. 122:1190, 2004). At 81 days postnatal (P81), eyes from AY9944-treated and control rats were enucleated, fixed in buffered mixed aldehydes, and processed for EM immunohistochemistry and computational molecular phenotyping (CMP) (J Comp Neurol. 464:1, 2003).
CMP of SLOS model retinas revealed progressive, but incomplete, retinal degeneration, with substantial loss of rod and cone photoreceptors. Spikes in aspartate concentration indicative of cell stress/death were seen in patches of photoreceptors. Aberrant sprouting of glycinergic amacrine cells was observed, as well as large stretches in the peripheral retina bereft of glycinergic or GABAergic amacrine cells. Punctate glutamate signals in the middle of the photoreceptor layer suggested aberrantly sprouting bipolar cells or photoreceptor processes. Müller cells exhibited signs of hypertrophy, plasticity and formation of the “Müller cell seal” with patches of increased glutamine and glutathione signals, consistent with prior observations of dramatic up-regulation of GFAP and gliosis in this model. DAPI labeling also showed non-uniform nuclear staining density (pyknosis) in populations of photoreceptors and bipolar cells, consistent with the observed loss of photoreceptors and retinal thinning.
Retinal remodeling, involving early retinal restructuring of both neuronal and glial populations, occurs in the AY9944 rat model of SLOS and is consistent with previous observations concerning retinal dysfunction and pathology in this model. Additionally, the marked variability in DAPI labeling among photoreceptor and bipolar cell populations suggests variations in DNA accessibility and, thus, gene expression, consistent with prior observations in the SLOS rat model.
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