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bioRxiv · 10.1101/2023.10.29.564225

Retinoic acid-dependent loss of synaptic output from bipolar cells impairs visual information processing in inherited retinal degeneration.

Ganzen, L.·Yadav, S. C.·Wei, M.·Ma, H.·Nawy, S.·Kramer, R.
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Abstract

In retinitis pigmentosa (RP), rod and cone photoreceptors degenerate, depriving downstream neurons of light-sensitive input, leading to vision impairment or blindness. Although downstream neurons survive, some undergo morphological and physiological remodeling. Bipolar cells (BCs) link photoreceptors, which sense light, to retinal ganglion cells (RGCs), which send information to the brain. While photoreceptor loss disrupts input synapses to BCs, whether BC output synapses remodel has remained unknown. Here we report that synaptic output from BCs plummets in RP mouse models of both sexes owing to loss of voltage-gated Ca2+ channels. Remodeling reduces the reliability of synaptic output to repeated optogenetic stimuli, causing RGC firing to fail at high stimulus frequencies. Fortunately, functional remodeling of BCs can be reversed by inhibiting the retinoic acid receptor (RAR). RAR inhibitors targeted to BCs present a new therapeutic opportunity for mitigating detrimental effects of remodeling on signals initiated either by surviving photoreceptors or by vision-restoring tools. Significance StatementPhotoreceptor degenerative disorders such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD) lead to vision impairment or blindness. Vision mediated by surviving photoreceptors or artificial vision restoration technologies, rely on bipolar cells retaining normal function despite photoreceptor death. We find that in two animal models of RP, synaptic transmission from both rod and cone bipolar cells is severely impaired owing to diminished voltage-gated calcium current, preventing postsynaptic amacrine cells and retinal ganglion cells from properly receiving and encoding visual information. We find that an inhibitor of the retinoic acid receptor restores both the calcium current and synaptic release from bipolar cells. These discoveries about bipolar cells reveal a new functional deficit in blindness and a potential therapeutically important solution.

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Ganzen, L., Yadav, S. C., Wei, M., Ma, H., Nawy, S., Kramer, R.. 2023-10-30. Retinoic acid-dependent loss of synaptic output from bipolar cells impairs visual information processing in inherited retinal degeneration.. https://doi.org/10.1101/2023.10.29.564225

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