Retinal Remodeling in a Rat Model of the Smith-Lemli-Opitz Syndrome (SLOS)

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This abstract was presented today at the Association for Research in Vision and Opthalmology (ARVO) meetings in Seattle, Washington by Steven J. Fliesler, Christopher C. Goulah, W. Drew Ferrell, Robert E. Marc and Bryan W. Jones.

Purpose:  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.

Methods:  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 computational molecular phenotyping (CMP) (J Neurosci. 15:5106, 1995; J Comp Neurol. 464:1, 2003).

Results:  CMP of SLOS model (AY9944-treated) retinas reveals progressive retinal degeneration with loss of rod and cone photoreceptors (PRs), although by P81, PR degeneration is not complete, since some rod/cone PRs remain. Spikes in aspartate concentration indicative of “cell stress/death” can be seen in patches of PRs. Aberrant sprouting of glycinergic amacrine cells (ACs) is observed, as well as large stretches in the peripheral retina bereft of glycinergic or GABAergic ACs. Punctate glutamate signals in the middle of the PR layer suggest aberrantly sprouting bipolar cells or PR processes. Müller cells also exhibit early signs of hypertrophy, plasticity and early formation of the Müller cell seal with patchy up-regulation in glutamine and glutathione signals, consistent with prior observations of dramatic up-regulation of GFAP and gliosis in this model. DAPI labeling also shows non-uniform nuclear staining density (pyknosis) in populations of PRs and bipolar cells, consistent with the observed loss of PRs and retinal thinning.

Conclusions:  Retinal remodeling, involving early retinal restructuring of both neuronal and glial populations, occurs in the AY9944-induced rat model of SLOS and is consistent with previous observations concerning retinal dysfunction and pathology in this model. Additionally, the large variations in DAPI labeling among photoreceptor and bipolar cell populations suggests large variations in DNA accessibility and, thus, gene expression, consistent with prior observations in this SLOS rat model.

Support:  This work was supported, in part, by U.S.P.H.S. (NEI/NIH) grants EY007361, EY002576, EY015128, EY014800 (Vision Core), by NSF grant 0941717, by facilities and resources provided by the Veterans Administration Western New York Healthcare System (SJF), by Unrestricted Grants from Research to Prevent Blindness (RPB) to the Depts of Ophthalmology (SUNY-Buffalo and Univ. of Utah), by an RPB Career Development Award (BWJ), and by a Thome Memorial Foundation Grant for AMD (BWJ).

A full size pdf of the poster can be downloaded here.