UC Berkeley

Azobenzene photoswitches confer light sensitivity onto retinal ganglion cells (RGCs) in blind mice, making these compounds promising candidates as vision-restoring drugs in humans with degenerative blindness. Remarkably, photosensitization manifests only in animals with photoreceptor degeneration and is absent in wild-type animals with intact rods and cones. While RGCs survive following photoreceptor death, they exhibit physiological changes, leading to heightened spontaneous activity and permissiveness to azobenzene photoswitch-reanimation. Here it is shown show that P2X receptors mediate photoswitch entry into RGCs where they associate with upregulated HCN channels, enabling light to control action potential firing. This remodeling is limited to morphologically identified OFF-RGCs, enabling selective and specific chemical photosensitization. This selectivity is not only for OFF-RGCs within a degenerated retina, but also displays selectivity within a focally degenerated retina, where photoreceptor death is non-uniform. Retinoic acid (RA), an important developmental morphogen, is also shown to be the signal that triggers pathophysiological retinal remodeling. Blocking RA signaling reduces remodeling and enhances light sensitivity in degenerating retinas. Enhancing RA signaling mimics pathophysiological remodeling in healthy retinas. A genetically-encoded fluorescent reporter shows increased RA signaling during degeneration. Identification of RA as the local, degeneration-dependent initiator of remodeling presents a new therapeutic opportunity for boosting low-level vision and performance of retinal prosthetics during degenerative blindness. Understanding the changes that occur in a degenerating retina and the signal for these changes has broad implications for disease-specific drug delivery.