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Juan Fernandez de Castro, James Demas, James Fransen, Paul DeMarco, Henry Kaplan, Maureen McCall; Changes in retinal ganglion cell activity in the P23H mini-swine model of retinal degeneration. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3386.
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© ARVO (1962-2015); The Authors (2016-present)
We have shown that transgenic (Tg) P23H swine expressing a mutant rhodopsin protein have most of the hallmarks of human retinitis pigmentosa. This study compared retinal ganglion cell (RGC) spontaneous and visually evoked activity in wild type (Wt) and Tg P23H piglets as a function of photoreceptor degeneration. Our results are critical to understanding changes in retinal processing and evaluating visual function using therapies targeted to replace photoreceptors or their function.
Eyes were enucleated from piglets (ages P30-P90), the retina immediately dissected under dim light and placed RGC layer down on a multi-electrode array in a heated chamber (30-32°C) with continuous perfusion of oxygenated Ames media. Spontaneous and light-evoked action potentials were recorded, stored data were sorted into individual RGC spike trains and their timestamps analyzed. Each RGC was classified as ON, OFF or non-responsive (NR) according to its response to full-field light stimulation whose intensity stimulated primarily rods (0.015 μW/cm2) or cones (0.15 and 1.5 μW/cm2). Because only a small number of RGCs had ON-OFF responses, they are excluded from this analysis.
The percentage of non-responsive RGCs (NR cells have spontaneous but no light evoked response) is low in Wt pigs and is invariant with age (P30 vs. P90; 12 vs. 13%). ON RGC responses dominate Wt retina at both ages (P30 vs. P90; ON = 75 vs. 85%). Wt RGC response thresholds are similar across age, although more ON RGCs respond to the lowest intensities compared to OFF RGCs (P30 vs. P90; 100% ON vs. 45% OFF). In contrast, a significant percentage of Tg RGCs are visually NR at both P30 and P90 (61 and 58%). Thresholds of Tg RGCs are significantly higher than Wt, none show rod driven responses, although Tg ON RGCs still tend to be more sensitive than Tg OFF RGCs (100% ON vs 63% OFF show responses to 0.15 μW/cm2 and 100% of ON cells respond to 1.5 μW/cm2). The predominance of Wt ON responses is significantly altered; only 27 vs 6% of visually responsive RGCs show ON responses in Tg retina at P30 vs. P90.
The lack of RGC activity after scotopic stimuli in the Tg correlates well with previously described full field ERG responses. In Tg pigs RGC ON responses are affected earlier than OFF responses. The design of therapeutic interventions needs to consider these functional changes in the inner retina.
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