Optogenetic vision restoration in the face of secondary and tertiary remodeling in the rd1 mouse retina

Photoreceptor loss in retinal degeneration is followed by progressive remodeling of the surviving retina, which may present a barrier to vision restoration. To determine the impact of remodeling on the retina's suitability for therapeutic interventions, we track changes in visual code produced by the optogenetic actuator ReaChR expressed in ON-bipolar cells of the rd1 mouse at 3, 5, 9, and 12 months. Anatomical analyses confirm that these ages encompass phase II (photoreceptor degeneration) to phase III (inner retinal thinning, dysmorphia, pigment epithelium infiltration) remodeling. Multi-electrode array recording from retinal ganglion cells reveals that ReaChR-driven responses to a range of visual stimuli are stable across this age range. Response amplitude, sensitivity, and reproducibility all increased between 3 and 5 months, remaining consistent thereafter. Receptive field sizes, contrast sensitivity, and temporal frequency tuning showed minor changes with age. The diversity of retinal ganglion cell coding was maintained, reflected by the diversity captured by unsupervised functional clustering, with 11 distinct visual channels retained across ages. Our data indicate that remodeling does not significantly impair, and at early stages may even enhance, the surviving retina's ability to support visual restoration. Clinical intervention thus remains viable throughout remodeling, suggesting a wide window in disease progression for therapeutic benefit.