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.

在色素性视网膜炎 (RP) 中，视杆细胞和视锥细胞光感受器退化，剥夺下游神经元的光敏感输入，导致视力障碍或失明。尽管下游神经元存活下来，但一些神经元经历了形态和生理重塑。双极细胞 (BC) 将感知光线的感光器与向大脑发送信息的视网膜神经节细胞 (RGC) 连接起来。虽然光感受器损失破坏了 BC 的输入突触，但 BC 输出突触是否重塑仍然未知。在这里，我们报告说，由于电压门控 Ca ²⁺通道的丢失，两性 RP 小鼠模型中 BC 的突触输出均急剧下降。重塑降低了突触输出对重复光遗传学刺激的可靠性，导致 RGC 放电在高刺激频率下失败。幸运的是，BC 的功能重塑可以通过抑制视黄酸受体 (RAR) 来逆转。针对 BC 的 RAR 抑制剂提供了一种新的治疗机会，可以减轻重塑对由幸存的光感受器或视力恢复工具引发的信号的不利影响。