Retinoic Acid causes degeneration-dependent electrophysiological remodeling of retinal ganglion cells and blocking its receptor augments vision in partially-blind mice

In retinal degeneration diseases such as Retinitis Pigmentosa (RP) and Age-Related Macular Degeneration (AMD) the photoreceptors die, but the inner retinal neurons survive. Importantly, retinal ganglion cells (RGCs), the only information output of the retina, remain connected to the brain. These cells undergo electrophysiological (fast) and morphological (slow) remodeling. Pathophysiological hyperactivity of RGCs reduces the signal-to-noise ratio, obscuring light-responses before degeneration is complete and precluding vision restoration in total blindness. Yet, despite decades of research into remodeling, the triggering signal has remained an open question. Our study shows that Retinoic Acid (RA) acting through its receptor (RAR), is that elusive trigger. Using a genetically-encoded double fluorescent reporter, we found that cells in the ganglion cell layer of degenerated retinas show increased RAR-mediated transcription as compared to healthy retinas. Increasing RAR activation in healthy retinas mimics remodeling, while blocking RAR in degenerated retinas rescues the phenotype. More importantly, pharmacological or genetic blockade of RAR reduces hyperactivity in mouse models of slow-progressing RP, unmasking retinal light responses and improving visually-oriented behavior. Furthermore, we found that RAR activation is behind similar electrophysiological changes in rat and monkey models of local degeneration, resembling AMD. Our results indicate that inhibiting RAR in degenerating retinas has the therapeutic potential of improving residual vision in partial blindness and enhancing vision-restoration technologies in total blindness.

References:

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