State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Sun Yat-sen University, Guangzhou 510060, China.
Sci Adv. 2024 Aug 2;10(31):eado0866. doi: 10.1126/sciadv.ado0866.
As part of the central nervous system, the optic nerve, composed of axons from retinal ganglion cells (RGCs), generally fails to regenerate on its own when injured in adult mammals. An innovative approach to promoting optic nerve regeneration involves manipulating the interactions between amacrine cells (ACs) and RGCs. Here, we identified a unique AC subtype, dopaminergic ACs (DACs), that responded early after optic nerve crush by down-regulating neuronal activity and reducing retinal dopamine (DA) release. Activating DACs or augmenting DA release with levodopa demonstrated neuroprotective effects and modestly enhanced axon regeneration. Within this context, we pinpointed the DA receptor D1 (DRD1) as a critical mediator of DAC-derived DA and showed that RGC-specific overexpression effectively overcame subtype-specific barriers to regeneration. This strategy markedly boosted RGC survival and axon regeneration after crush and preserved vision in a glaucoma model. This study unveils the crucial role of DAC-derived DA signaling in optic nerve regeneration, holding promise for therapeutic insights into neural repair.
作为中枢神经系统的一部分，视神经由视网膜神经节细胞（RGCs）的轴突组成，在成年哺乳动物中受伤时通常无法自行再生。一种促进视神经再生的创新方法涉及操纵无长突细胞（ACs）和 RGCs 之间的相互作用。在这里，我们鉴定出一种独特的 AC 亚型，多巴胺能 ACs（DACs），在视神经挤压后通过下调神经元活性和减少视网膜多巴胺（DA）释放而早期反应。激活 DACs 或用左旋多巴增强 DA 释放显示出神经保护作用，并适度增强轴突再生。在这种情况下，我们确定了多巴胺受体 D1（DRD1）作为 DAC 衍生 DA 的关键介质，并表明 RGC 特异性过表达可有效克服再生的亚型特异性障碍。这种策略在挤压后显著提高了 RGC 的存活和轴突再生，并在青光眼模型中保留了视力。这项研究揭示了 DAC 衍生的 DA 信号在视神经再生中的关键作用，为神经修复的治疗见解提供了希望。
