Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA, USA.
Sci Adv. 2022 Mar 18;8(11):eabm4643. doi: 10.1126/sciadv.abm4643.
Rod and cone photoreceptors degenerate in retinitis pigmentosa (RP). While downstream neurons survive, they undergo physiological changes, including accelerated spontaneous firing in retinal ganglion cells (RGCs). Retinoic acid (RA) is the molecular trigger of RGC hyperactivity, but whether this interferes with visual perception is unknown. Here, we show that inhibiting RA synthesis with disulfiram, a deterrent of human alcohol abuse, improves behavioral image detection in vision-impaired mice. In vivo Ca imaging shows that disulfiram sharpens orientation tuning of visual cortical neurons and strengthens fidelity of responses to natural scenes. An RA receptor inhibitor also reduces RGC hyperactivity, sharpens cortical representations, and improves image detection. These findings suggest that photoreceptor degeneration is not the only cause of vision loss in RP. RA-induced corruption of retinal information processing also degrades vision, pointing to RA synthesis and signaling inhibitors as potential therapeutic tools for improving sight in RP and other retinal degenerative disorders.
杆状和锥状光感受器在色素性视网膜炎（RP）中退化。虽然下游神经元存活，但它们会发生生理变化，包括视网膜神经节细胞（RGC）自发性放电加速。视黄酸（RA）是 RGC 过度活跃的分子触发因素，但这是否会干扰视觉感知尚不清楚。在这里，我们表明，用双硫仑（一种抑制人类滥用酒精的药物）抑制 RA 合成可以改善视力受损小鼠的行为图像检测。体内 Ca 成像表明，双硫仑可锐化视觉皮层神经元的方位调谐，并增强对自然场景反应的保真度。RA 受体抑制剂也可减少 RGC 过度活跃，锐化皮质代表，并改善图像检测。这些发现表明，光感受器退化并不是 RP 中视力丧失的唯一原因。RA 诱导的视网膜信息处理腐败也会降低视力，这表明 RA 合成和信号抑制剂可能是改善 RP 和其他视网膜退行性疾病视力的潜在治疗工具。
