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T. J. McGill, G. T. Prusky, M. M. LaVail, G. Luna, S. K. Fisher, G. P. Lewis; Early Retinal Reorganization May Cause Visual Abnormalities in Rhodopsin Transgenic Rats. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2987. doi: https://doi.org/.
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Previous studies report that transgenic rats with the S334ter-4 rhodopsin mutation do not exhibit significant retinal reorganization until late stages of retinal degeneration. In addition, electroretinogram (ERG) a- and b-wave amplitudes and outer nuclear layer (ONL) thickness measurements, which are near normal until postnatal day 60 (P60), do not predict deficits in behaviorally measured visual thresholds which appear ~P20. Therefore, the purpose of the present study was to determine if more sensitive sampling methods could detect early non-adaptive reorganization of the retina that could account for the discrepancies between ERG and behavioral measurements.
Age-matched Long-Evans and S334ter line 4 transgenic rats were used. Eyes were removed at ages ranging from P15 to P40, immersion fixed in 4% paraformaldehyde, embedded in agarose and subsequently sectioned at 100 µm. Sections were labeled with various antibodies to proteins in photoreceptors, second and third order neurons, synaptic vesicles and ribbons, and glial and microglial cells. Their distribution was determined using an Olympus FluoView confocal microscope.
Long-Evans rats exhibited a typical developmental shift in ribbon formation and opsin expression between P15 and P30: synaptic ribbons in the OPL changed from a rounded appearance to their normal crescent shape. Rod opsin levels were initially elevated in the ONL but became restricted to the outer segments. S334ter-4 rats, however, exhibited persistent abnormal synaptic terminals (anti-synaptophysin and -CtbP2) and continuous rod opsin expression was found throughout the ONL. Glial growth (anti-GFAP and vimentin) into the subretinal space and microglial cell activation (Isolectin B4) were evident by P30. Horizontal cell neurite outgrowth (anti-neurofilament) into the ONL was evident by P40.
Early retinal reorganization in S334ter line 4 rats is evident shortly before behavioral deficits are observed. These data suggest that significant cellular and molecular changes occur before gross anatomical changes are evident, and that these changes may non-adaptively affect retinal function.
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