Department of Neurobiology of Rhythms, CNRS UPR 3212 Institute of Cellular and Integrative Neurosciences, Strasbourg, France.
Neuroscience. 2010 Sep 15;169(4):1815-30. doi: 10.1016/j.neuroscience.2010.06.037. Epub 2010 Jun 22.
Cone photoreceptor breakdown underlies functional vision loss in many blinding diseases. Cone loss is often secondary to that of rods, but little experimental data are available on the relationship between the two populations. Because of its high cone numbers, we used the diurnal rodent Arvicanthis ansorgei to explore changes in rod and cone survival and function during chemically-induced retinal degeneration. Adult animals received intraperitoneal injections of N-methyl-N-nitrosourea (MNU), and changes in retinal fundus appearance, histology, phenotype, apoptosis (TUNEL staining) and functionality (scotopic and photopic electroretinography) were monitored as a function of post-treatment time and retinal topography. Relative to control animals injected with vehicle only, MNU-injected animals showed time-, region- and population-specific changes as measured by morphological and immunochemical criteria. Histological (gradual thinning of photoreceptor layer) and phenotypical (reduced immunostaining of rhodopsin and rod transducin, and mid wavelength cone opsin and cone arrestin) modifications were first observed in superior central retina at 11 days post-injection. These degenerative changes spread into the superior peripheral and inferior hemisphere during the following 10 days. Rod loss preceded that of cones as visualized by differential immunolabelling and presence of apoptotic cells in rod but not cone cells. By 3 months post-injection, degeneration of the photoreceptor layer was complete in the superior hemisphere, but only partial in the inferior hemisphere. Despite the persistence of cone photoreceptors, scotopic and photopic electroretinography performed at 90 days post-treatment showed that both rod and cone function were severely compromised. In conclusion, MNU-induced retinal degeneration in Arvicanthis follows a predictable spatial and temporal pattern allowing clear separation of rod- and cone-specific pathogenic mechanisms. Compared to other rodents in which MNU has been used, Arvicanthis ansorgei demonstrates pronounced resistance to photoreceptor cell loss.
圆锥细胞的破坏是许多致盲性疾病中功能性视力丧失的基础。圆锥细胞的损失通常继发于杆状细胞，但关于这两种细胞群体之间的关系，实验数据很少。由于其高圆锥细胞数量，我们使用昼行性啮齿动物非洲沙鼠来探索化学诱导的视网膜变性过程中杆状细胞和圆锥细胞的存活和功能变化。成年动物接受腹腔注射 N-甲基-N-亚硝脲（MNU），并根据治疗后时间和视网膜拓扑结构监测视网膜眼底外观、组织学、表型、细胞凋亡（TUNEL 染色）和功能（暗适应和明适应视网膜电图）的变化。与仅注射载体的对照动物相比，MNU 注射动物表现出时间、区域和群体特异性变化，这是通过形态学和免疫化学标准测量的。组织学（光感受器层逐渐变薄）和表型（视紫红质和杆状细胞转导蛋白以及中波视锥细胞 opsin 和视锥细胞 arrestin 的免疫染色减少）改变首先在注射后 11 天观察到中上部中央视网膜。这些退行性变化在随后的 10 天内扩散到上外周和下半球。通过差异免疫标记和仅在杆状细胞而不是视锥细胞中存在凋亡细胞来观察到杆状细胞的丢失早于视锥细胞的丢失。在注射后 3 个月，上半球的光感受器层完全变性，但下半球仅部分变性。尽管视锥细胞仍然存在，但在治疗后 90 天进行的暗适应和明适应视网膜电图显示，杆状细胞和视锥细胞的功能都严重受损。总之，非洲沙鼠的 MNU 诱导的视网膜变性遵循可预测的时空模式，允许清晰分离杆状细胞和视锥细胞特异性的致病机制。与其他已使用 MNU 的啮齿动物相比，非洲沙鼠对光感受器细胞丧失表现出明显的抗性。
