Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, California 94720.
Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, California 94720
J Neurosci. 2024 Aug 28;44(35):e0129242024. doi: 10.1523/JNEUROSCI.0129-24.2024.
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 Ca 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.
在视网膜色素变性（RP）中，视杆和视锥感光细胞退化，剥夺了下游神经元对光敏感的输入，导致视力损害或失明。尽管下游神经元存活下来，但有些神经元会发生形态和生理重塑。双极细胞（BC）将感光器（感知光线）与视网膜神经节细胞（RGC）连接起来，后者将信息发送到大脑。虽然光感受器的丧失破坏了向 BC 的输入突触，但 BC 输出突触是否发生重塑仍不清楚。在这里，我们报告称，由于电压门控钙通道的丧失，两性 RP 小鼠模型中 BC 的突触输出急剧下降。重塑降低了对重复光遗传学刺激的突触输出的可靠性，导致 RGC 在高刺激频率下放电失败。幸运的是，BC 的功能重塑可以通过抑制维甲酸受体（RAR）来逆转。针对 BC 的 RAR 抑制剂为减轻由幸存的光感受器或通过恢复视力的工具引发的重塑对信号的不利影响提供了新的治疗机会。
