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B.A. Johnson, S. Ikeda, L.H. Pinto, A. Ikeda; Aberrant Synaptic Localization and Schisis Caused by a Splice Site Mutation in the Rs1h Gene . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4580.
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X–Linked Retinoschisis (XLRS) is a leading cause of inherited macular degeneration in male children caused by mutations in the RS1 gene. Affected individuals show a significant loss in central vision, a splitting of the inner layers of the retina, and a loss in the ERG b–wave. Rs1htmgc1 mice, which have a splice site mutation in the RS1 homologue, Rs1h, were generated by the Tennessee Mouse Genome Consortium ENU neuromutagenesis project. The purpose of this study was to determine the role of Rs1h in synaptic structure and function, through morphological and electrophysiological analyses of the Rs1htmgc1 retina.
To examine the synaptic structure of the outer plexiform layer (OPL) in adult Rs1htmgc1 retina, we performed a detailed analysis using pre– and post–synaptic markers. The role of Rs1h on cone cell structure was examined by crossing Rs1htmgc1 mice to mice carrying a GFP transgene that expresses in cone cells. Retinal synapses were also examined ultrastructurally using electron microscopy. To examine the role of Rs1h during development, we analyzed the schisis and synaptic phenotypes at multiple developmental time points. Electroretinograms (ERGs) were recorded from wild–type and Rs1htmgc1 mice at both four weeks and nine weeks of age.
In adult Rs1htmgc1 mice, the structure of the outer plexiform layer is disorganized. Second–order neurons ectopically extend neurites into the outer nuclear layer (ONL) and photoreceptor presynapses are ectopically localized in the ONL. Synaptic structure and function of both rods and cones are affected in Rs1htmgc1 mice. Morphological defects are first observed at P17, after the photoreceptor synapse has completed development at P14. The schisis phenotype is most severe at four weeks of age but then gradually becomes less severe until no apparent schisis is observed at ten weeks of age. ERG analysis showed that the b–wave amplitude is greatly reduced while the a–wave is normal in four weeks old Rs1htmgc1 mice.
Rs1h plays an important role in the structure and function of the photoreceptor synapses. The reduction in b–wave amplitude compared with the preservation of the a–wave amplitude suggests that a primary effect of this mutation is in the neurotransmission from photoreceptor cells to second–order neurons, or the function of the second–order neurons. Morphological analysis in Rs1htmgc1 suggests that Rs1h is important for the maintenance of the synaptic structure of both cone and rod cells.
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