Mammalian retinal degenerations initiated by gene defects in rods, cones or the retinal pigmented epithelium (RPE) often trigger loss of the sensory retina, effectively leaving the neural retina deafferented. The neural retina responds to this challenge by remodeling, first by subtle changes in neuronal structure and later by large-scale reorganization. Retinal degenerations in the mammalian retina generally progress through three phases. Phase 1 initiates with expression of a primary insult, followed by phase 2 photoreceptor death that ablates the sensory retina via initial photoreceptor stress, phenotype deconstruction, irreversible stress and cell death, including bystander effects or loss of trophic support. The loss of cones heralds phase 3: a protracted period of global remodeling of the remnant neural retina. Remodeling resembles the responses of many CNS assemblies to deafferentation or trauma, and includes neuronal cell death, neuronal and glial migration, elaboration of new neurites and synapses, rewiring of retinal circuits, glial hypertrophy and the evolution of a fibrotic glial seal that isolates the remnant neural retina from the surviving RPE and choroid. In early phase 2, stressed photoreceptors sprout anomalous neurites that often reach the inner plexiform and ganglion cell layers. As death of rods and cones progresses, bipolar and horizontal cells are deafferented and retract most of their dendrites. Horizontal cells develop anomalous axonal processes and dendritic stalks that enter the inner plexiform layer. Dendrite truncation in rod bipolar cells is accompanied by revision of their macromolecular phenotype, including the loss of functioning mGluR6 transduction. After ablation of the sensory retina, Müller cells increase intermediate filament synthesis, forming a dense fibrotic layer in the remnant subretinal space. This layer invests the remnant retina and seals it from access via the choroidal route. Evidence of bipolar cell death begins in phase 1 or 2 in some animal models, but depletion of all neuronal classes is evident in phase 3. As remodeling progresses over months and years, more neurons are lost and patches of the ganglion cell layer can become depleted. Some survivor neurons of all classes elaborate new neurites, many of which form fascicles that travel hundreds of microns through the retina, often beneath the distal glial seal. These and other processes form new synaptic microneuromas in the remnant inner nuclear layer as well as cryptic connections throughout the retina. Remodeling activity peaks at mid-phase 3, where neuronal somas actively migrate on glial surfaces. Some amacrine and bipolar cells move into the former ganglion cell layer while other amacrine cells are everted through the inner nuclear layer to the glial seal. Remodeled retinas engage in anomalous self-signaling via rewired circuits that might not support vision even if they could be driven anew by cellular or bionic agents. We propose that survivor neurons actively seek excitation as sources of homeostatic Ca(2+) fluxes. In late phase 3, neuron loss continues and the retina becomes increasingly glial in composition. Retinal remodeling is not plasticity, but represents the invocation of mechanisms resembling developmental and CNS plasticities. Together, neuronal remodeling and the formation of the glial seal may abrogate many cellular and bionic rescue strategies. However, survivor neurons appear to be stable, healthy, active cells and given the evidence of their reactivity to deafferentation, it may be possible to influence their emergent rewiring and migration habits.

中文翻译：

---

视网膜变性中的神经重塑。

由视杆细胞、视锥细胞或视网膜色素上皮 (RPE) 中的基因缺陷引发的哺乳动物视网膜变性通常会引发感觉视网膜的丧失，从而有效地使神经视网膜失传。神经视网膜通过重塑来应对这一挑战，首先是通过神经元结构的细微变化，然后是大规模重组。哺乳动物视网膜中的视网膜变性通常经历三个阶段。第 1 阶段以初级损伤的表达开始，然后是第 2 阶段光感受器死亡，通过最初的光感受器压力、表型解构、不可逆的压力和细胞死亡（包括旁观者效应或营养支持的丧失）消融感觉视网膜。视锥细胞的丧失预示着第 3 阶段：残余神经视网膜的全球重塑的长期期。重塑类似于许多 CNS 组件对传入神经阻滞或创伤的反应，包括神经元细胞死亡、神经元和神经胶质迁移、新神经突和突触的形成、视网膜回路的重新布线、神经胶质肥大和分离残余物的纤维化神经胶质密封的进化来自幸存的 RPE 和脉络膜的神经视网膜。在第 2 阶段的早期，受压的光感受器会长出异常的神经突，这些神经突通常会到达内部丛状细胞层和神经节细胞层。随着视杆细胞和视锥细胞死亡的进展，双极细胞和水平细胞被去传入并收回它们的大部分树突。水平细胞发育出异常的轴突和进入内丛状层的树突状茎。杆状双极细胞中的树突截断伴随着其大分子表型的修正，包括失去功能的 mGluR6 转导。感觉视网膜消融后，Müller 细胞增加中间丝合成，在残余的视网膜下空间形成致密的纤维化层。该层覆盖剩余的视网膜并将其密封，使其无法通过脉络膜途径进入。在某些动物模型中，双极细胞死亡的证据始于第 1 或第 2 阶段，但在第 3 阶段，所有神经元类别的消耗都很明显。随着重塑在数月和数年内进行，更多的神经元丢失，神经节细胞层的斑块可能会耗尽. 所有类别的一些幸存者神经元都形成了新的神经突，其中许多形成了束，通过视网膜行进数百微米，通常位于远端神经胶质密封下方。这些和其他过程在残余内核层中形成新的突触微神经瘤以及整个视网膜的隐秘连接。重塑活动在第 3 阶段中期达到顶峰，此时神经元胞体在神经胶质表面积极迁移。一些无长突细胞和双极细胞进入前神经节细胞层，而其他无长突细胞通过内核层外翻到神经胶质密封。重塑的视网膜通过重新布线的电路进行异常的自我信号传导，即使它们可以由细胞或仿生剂重新驱动，这些电路也可能不支持视觉。我们建议幸存者神经元积极寻求激发作为稳态 Ca(2+) 通量的来源。在第 3 阶段后期，神经元继续丢失，视网膜的胶质成分越来越多。视网膜重塑不是可塑性，但代表了类似于发育和中枢神经系统可塑性的机制的调用。总之，神经元重塑和胶质密封的形成可能会废除许多细胞和仿生救援策略。然而，幸存者神经元似乎是稳定、健康、活跃的细胞，并且鉴于它们对去传入神经的反应性的证据，有可能影响它们出现的重新布线和迁移习惯。