Mathematical analysis of photoreceptor changes in conditions of separation from the underlying retinal pigment epithelium.

Photoreceptors (PR) are responsible for absorbing and converting light into electrical signals necessary to create vision. To accomplish that, they are in an intimate relationship and attached to the underlying retinal pigment epithelium (RPE). Separation of the PR from the underlying RPE is seen in many retina disorders and leads to PR cell death and subsequent vision loss. Separation of PR from the RPE (detachment) interferes with the normal phagocytosis and recycling of PR outer segments by the RPE, and disrupts nutrient and metabolite delivery, including glucose. All these factors contribute to cell dysfunction and eventual cell death. In this work, we sought to understand the importance of different factors in PR cell loss after detachment using mathematical modeling. We used known information of photoreceptor interactions in the healthy retina from the literature, and datasets for rod and cone degeneration after detachment. We also included three additional published datasets of PR cell death kinetics. A mathematical sensitivity analysis examined the impact of the parameters on the system over a detachment of 150 days and found that the parameters that significantly impact the rod and the cone population at the stages where "early intervention" happens (3-7 days after detachment) are not always the same ones that significantly impact the populations at 150 days. Additionally, some of the parameters negatively affected one population while having the opposite effect on the other. An increase in nutrient availability and efficiency of rod energy uptake were the only parameters that did not have a negative effect on either population. Similar results were obtained for reattachment. The interplay between these variables indicates that effective photoreceptor neuroprotection in retinal detachment may require multiple strategies. The prediction of these impactful parameters over time can be further assessed in experimental models and may provide guidance on the most effective ways to improve PR survival after their separation from RPE.