R 1 7 8 9 10 11 12 13 14 Loss of responses to visual but not electrical stimulation in ganglion cells of rats with 15 severe photoreceptor degeneration 16 17 18 19

31 32 Retinal implants are intended to help patients with degenerative conditions by electrically 33 stimulating surviving cells to produce artificial vision. However, little is known about how 34 individual retinal ganglion cells respond to direct electrical stimulation in degenerating retina. 35 Here we used a transgenic rat model to characterize ganglion cell responses to light and 36 electrical stimulation during photoreceptor degeneration. Retinas from pigmented P23H-1 rats 37 were compared to wild-type retinas between ages P37 and P752. During degeneration, retinal 38 thickness declined by 50%, largely as a consequence of photoreceptor loss. Spontaneous 39 electrical activity in retinal ganglion cells initially increased 2-3 fold, but returned to nearly 40 normal levels around P600. A profound decrease in the number of light-responsive ganglion 41 cells was observed during degeneration, culminating in retinas without detectable light 42 responses by P550. Ganglion cells from transgenic and wild-type animals were targeted for 43 focal electrical stimulation using multi-electrode arrays with electrode diameters of ~10 44 microns. Ganglion cells were stimulated directly, and the success rate of stimulation in both 45 groups was 60-70% at all ages. Surprisingly, thresholds (~0.05 mC/cm) and latencies (~0.25 46 ms) in P23H rat ganglion cells were comparable to those in wild-type ganglion cells at all 47 ages, and showed no change over time. Thus, ganglion cells in P23H rats respond normally to 48 direct electrical stimulation despite severe photoreceptor degeneration and complete loss of 49 light responses. These findings suggest that high-resolution epiretinal prosthetic devices may 50 be effective in treating vision loss resulting from photoreceptor degeneration. 51