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Naheed W. Khan, Ashley Moncrief, Garrett W. Grahek, John R. Heckenlively; Inner Retinal Function and Structure in a Mouse Model (Rd9) of X-linked Retinitis Pigmentosa. Invest. Ophthalmol. Vis. Sci. 2012;53(14):6445.
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To understand the relationship between inner retinal function and inner retinal structure in the Rd9/y mouse as a model of X-linked Retinitis Pigmentosa (XLRP), which is one of the most severe forms of retinal degeneration.
Male Rd9/y and C57BL/6 control mice were studied at ages 2, 12, and 24 months by flash electroretinograms (ERGs) and correlative retinal histology. Inner retinal function isolated from scotopic and photopic ERGs was assessed using the scotopic threshold response (STR), the sum of amplitudes of the first six oscillatory potentials (OPs) extracted from the maximal dark-adapted ERG response at1.09 log cd.s/m2, and the photopic negative response (PhNR). Response amplitudes of the positive STR (pSTR) and negative STR (nSTR) were measured at 110 ms and 200 ms respectively. For histology analysis, thicknesses of the inner nuclear layer (INL), inner plexiform layer (IPL) and the ganglion cell layer (GCL) were measured at fixed distances from the optic nerve head in the superior, inferior, temporal, and nasal retina.
Scotopic ERG a- and b-wave and the photopic b-wave amplitudes of Rd9/y mice were lower than control for all ages. At 24 months all amplitudes were reduced by 65% from control, but waveform morphology was intact. The pSTR and nSTR were comparable with wild-type at 12 months. At 24 months, the pSTR of Rd9/y mice was diminished and the nSTR threshold was elevated by 0.5 to 1.0 log units. Sum of OP amplitudes was reduced by 40% from control at later ages. PhNR amplitude was consistently lower by about 35% than in wild-type mice at all ages. By 24 months, the Rd9/y PhNR was reduced by 30% from the amplitude at 2 months. Morphological analysis showed concordance between age-dependent decline in ERG a- and b-wave amplitudes and thinning of photoreceptor inner and outer segments and outer nuclear layer. By 24 months, the Rd9/y mouse photoreceptor layer was approximately half the thickness at 2 months. By contrast, a reverse relationship was observed between inner retinal ERG parameters and thickness of INL, IPL, and GCL. From 2 months to 12 months age, INL, IPL, and GCL thickness in Rd9/y mice were comparable to wild-type. At later ages, the wild-type INL, IPL and GCL thickness decreased but the Rd9/y mice showed no further thinning after 12 months.
The Rd9/y mouse shows relative preservation of inner retinal structure and function despite age-dependent gradual loss of photoreceptor and outer nuclear layer thickness. The apparent lack of inner retinal cell loss in Rd9/y mice may be attributed to an increased thickening due to neuronal-glial remodeling. The relatively slow rate of loss of function in the Rd9/y mouse offers a wide time frame to test therapeutic interventions.
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