Inhibitory Circuits Can Restore OFF Pathway Responses in Retinal Prostheses.

One of the first steps in processing visual information is to split the light signal captured by photoreceptors into complementary ON and OFF pathways, which separately encode increases and decreases in luminance. In blind patients with retinal degeneration, optoelectronic prostheses can successfully activate the ON pathway and evoke bright percepts; however, patients do not perceive dark features. This indicates that the OFF pathway is not being activated by existing prosthetics. To quantify OFF pathway deficits, we stimulated retinal ganglion cells (RGCs) in a mouse model of retinitis pigmentosa of either sex with electrical stimulation mimicking retinal prosthetic activation and recorded their voltage responses using whole-cell recording. We found that most OFF RGCs respond with incorrect ON responses, except for one specific subtype of RGC, the OFFα, which retained correct OFF-type responses following the termination of stimulation. We found that these preserved OFF responses were driven by postinhibitory rebound excitation, mediated by hyperpolarization-activated cyclic nucleotide-gated channels. Using a combinatorial genetic approach to achieve chemogenetic control, we identified AII amacrine cells as the presynaptic source driving these electrically evoked OFF responses. These insights into how the OFF pathway responds to artificial stimulation suggest new opportunities to improve prosthetic vision restoration through tuning of stimulation parameters.