Photoreceptor degeneration has heterogeneous effects on functional retinal ganglion cell types

Abstract

Retinitis pigmentosa is a hereditary disease causing progressive degeneration of rod and cone photoreceptors, with no effective therapies. Using the rd10 mouse model, which mirrors the human condition, we examined its disease progression. Rods deteriorate by postnatal day (P) 45, followed by cone degeneration, with most photoreceptors lost by P180. Until then, retinal ganglion cells (RGCs) remain light-responsive, albeit only under photopic conditions, despite extensive outer retinal remodelling. However, it is still unknown whether the different functional RGC types remain stable, or if some types differentially alter their activity or are even lost during disease progression. Here, we addressed if and how the response diversity of functional RGC types changes with rd10 disease progression. At P30, we were able to identify all functional wild-type RGC types also in rd10 retina, suggesting that at this early degenerative stage, the full breadth of retinal output is still present. Remarkably, we found that the fractions of functional types changed throughout progressing degeneration between rd10 and wild-type: Responses of RGCs with ‘Off’-components (‘Off’ and ‘On-Off’ RGCs) seemed to be more vulnerable than ‘On’-cells, with ‘Fast-On’ types being the most resilient. Notably, direction-selective RGCs appeared to be more vulnerable than orientation-selective RGCs. In summary, we found differences in resilience of response types (from resilient to vulnerable): ‘Uncertain’ > ‘Fast On’ > ‘Slow On’ > ‘On-Off’ > ‘Off’. Taken together, our results suggest that rd10 photoreceptor degeneration has heterogeneous effects on functional RGC types, with distinct sets of types losing their characteristic light responses earlier than others. This differential susceptibility of RGC circuits may be of relevance for future neuroprotective therapeutic strategies.