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 rd10 mice, which mirror 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 under photopic conditions, despite extensive outer retinal remodelling. However, it is still unknown if distinct functional RGC types alter their activity or are even lost during disease progression. Here, we asked if and how the response diversity of functional RGC types changes with rd10 disease progression. At P30, we identified all functional wild-type RGC types also in rd10 retinae, 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) were 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.

Key points

• Retinitis pigmentosa is a hereditary disease causing progressive degeneration of rod and cone photoreceptors, with no effective therapies; it can be investigated using mutant mouse models, like rd10, that mirror the human condition.
• Recent studies found that retinal ganglion cells (RGCs) in rd10 remain light-responsive, despite extensive loss of photoreceptors and outer retinal remodelling; however, specific RGC types still may change or even lose their functional response profile during early degeneration.
• Using two-photon calcium imaging, we assessed if and how the light-evoked activity of RGCs, and, hence, the retinal output to the brain, differs during the disease progression in rd10 compared to wild-type mice.
• We found differences in the resilience of functional RGC types: generally, ‘On’-types were more resilient than ‘On–Off’ or especially ‘Off’ types.
• Our data suggest that interventions may be more effective in the ‘On’ pathways, which turned out to be more resilient in rd10.