Jones Bryan W, Watt Carl B, Frederick Jeanne M, Baehr Wolfgang, Chen Ching-Kang, Levine Edward M, Milam Ann H, Lavail Matthew M, Marc Robert E
John A. Moran Eye Center, University of Utah School of Medicine, Salt Lake City, Utah 84132.
J Comp Neurol. 2003 Sep 8;464(1):1-16. doi: 10.1002/cne.10703.
Many photoreceptor degenerations initially affect rods, secondarily leading to cone death. It has long been assumed that the surviving neural retina is largely resistant to this sensory deafferentation. New evidence from fast retinal degenerations reveals that subtle plasticities in neuronal form and connectivity emerge early in disease. By screening mature natural, transgenic, and knockout retinal degeneration models with computational molecular phenotyping, we have found an extended late phase of negative remodeling that radically changes retinal structure. Three major transformations emerge: 1) Müller cell hypertrophy and elaboration of a distal glial seal between retina and the choroid/retinal pigmented epithelium; 2) apparent neuronal migration along glial surfaces to ectopic sites; and 3) rewiring through evolution of complex neurite fascicles, new synaptic foci in the remnant inner nuclear layer, and new connections throughout the retina. Although some neurons die, survivors express molecular signatures characteristic of normal bipolar, amacrine, and ganglion cells. Remodeling in human and rodent retinas is independent of the initial molecular targets of retinal degenerations, including defects in the retinal pigmented epithelium, rhodopsin, or downstream phototransduction elements. Although remodeling may constrain therapeutic intervals for molecular, cellular, or bionic rescue, it suggests that the neural retina may be more plastic than previously believed.
许多光感受器退化最初影响视杆细胞，继而导致视锥细胞死亡。长期以来，人们一直认为存活的神经视网膜在很大程度上对这种感觉传入缺失具有抗性。来自快速视网膜退化的新证据表明，神经元形态和连接性的细微可塑性在疾病早期就会出现。通过用计算分子表型分析筛选成熟的自然、转基因和基因敲除视网膜退化模型，我们发现了一个延长的负性重塑晚期阶段，该阶段从根本上改变了视网膜结构。出现了三种主要转变：1）穆勒细胞肥大以及视网膜与脉络膜/视网膜色素上皮之间远端胶质密封的形成；2）明显的神经元沿着胶质表面迁移到异位部位；3）通过复杂神经突束的进化、残余内核层中新的突触灶以及整个视网膜中新的连接进行重新布线。尽管一些神经元死亡，但存活的神经元表达出正常双极细胞、无长突细胞和神经节细胞特有的分子特征。人类和啮齿动物视网膜中的重塑与视网膜退化的初始分子靶点无关，包括视网膜色素上皮、视紫红质或下游光转导元件的缺陷。尽管重塑可能会限制分子、细胞或仿生救援的治疗间隔，但它表明神经视网膜可能比以前认为的更具可塑性。
