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

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 is unknown. Here we report that synaptic output from BCs plummets in mouse models of RP owing to loss of voltage-gated Ca2+channels. Remodeling reduces the dynamic range and the reliability of the BC output synapse to repeated optogenetic stimuli, eliminating RGC firing at high stimulus frequencies. However, the consequences of functional BC remodeling 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 by surviving photoreceptors or vision-restoring tools.