Variability in Depolarization Sensitivity Underlies Differential Responses to High-frequency Stimulation of ON and OFF RGCs

Retinal prostheses aim to restore vision to patients with outer retinal degeneration, but the quality of restored vision is still far below that of the healthy visual system. Although multiple factors are likely to contribute to this limited effectiveness, the inability to reproduce the complex neural coding patterns that arise naturally in the retina, e.g., the indiscriminate activation of diverse types of retinal ganglion cells (RGCs) by electric stimulation, is likely to play a significant role. Our previous research has shown that different types of RGCs can be preferentially activated by modulating the stimulus amplitude of high-frequency stimulation (HFS). As a step towards optimizing selectivity, our goal was to explore mechanisms underlying the sensitivity differences between cell types. By measuring responses of RGCs to 2 kHz stimulation with the whole-cell patch technique, we found that increasing the amplitude of stimulation led to greater depolarization of membrane potentials. While small increases in the depolarization level increased spike rates, excessive depolarization suppressed spiking activities. Subsequent comparison between ON and OFF a sustained RGCs revealed that ON cells are more depolarized by a given amplitude of HFS than OFF cells, resulting in stronger responses of ON cells at lower amplitudes but suppression of ON cell spiking at higher amplitudes. Our results suggest that a better understanding of the changes in membrane potential induced by HFS is essential to further optimize HFS-based strategies for retinal prosthesis.