Bascom Palmer Eye Institute, University of Miami, Miller School of Medicine, Miami, Florida, United States.
Retinal Ganglion Cell Biology Section, Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States.
Invest Ophthalmol Vis Sci. 2014 Aug 14;55(9):5602-9. doi: 10.1167/iovs.14-14793.
To characterize age-related changes of retinal ganglion cell (RGC) function, IOP, and anatomical markers of axon/glia integrity in a transgenic mouse expressing Tyr437His mutant of human myocilin protein.
Retinal ganglion cell electrical responsiveness was tested with pattern electroretinogram (PERG) in 11 transgenic mice expressing mutated myocilin at different ages over 18 months under ketamine/xylazine anesthesia. Twelve age-matched C57BL/6J mice also were tested as controls. Intraocular pressure was measured with a Tonolab tonometer. Immunohistochemistry for GFAP and neurofilament was performed on dissected optic nerve heads.
In transgenic mice expressing mutated myocilin, the PERG amplitude progressively decreased with increasing age by approximately 50%, whereas the PERG peak latency increased by approximately 40 ms (ANOVA, P < 0.05). In contrast, PERGs of young and old control mice had similar amplitudes and peak latencies. In transgenic mice, GFAP staining was more intense and extended than in control mice, and increased with increasing age; neurofilament staining showed swollen and partially degenerated axons in old transgenic mice. The IOP of young transgenic mice was similar to that of control mice and did not significantly change with increasing age.
Transgenic mice expressing mutated human myocilin display progressive age-related changes in RGC electrical responsiveness that are not associated with IOP elevation but are associated with marked astrogliosis and axonopathy. Our results support the view that MYOC expression in the optic nerve may impact structural, metabolic, or neurotrophic support to RGC axons, thereby influencing their susceptibility to glaucomatous damage independently of IOP.
为了描述表达人类突变型肌球蛋白的转基因小鼠中视网膜神经节细胞（RGC）功能、眼内压（IOP）和轴突/胶质完整性的解剖学标记物的年龄相关性变化，我们进行了此项研究。
在 11 只表达突变型肌球蛋白的转基因小鼠中，通过在氯胺酮/甲苯噻嗪麻醉下进行图形视网膜电图（PERG）测试，研究了不同年龄的 RGC 的电反应性。此外，我们还对 12 只年龄匹配的 C57BL/6J 小鼠进行了测试作为对照。使用眼压计（Tonolab）测量 IOP。对解剖的视神经头部进行 GFAP 和神经丝免疫组织化学染色。
在表达突变型肌球蛋白的转基因小鼠中，PERG 幅度随年龄的增加而逐渐降低约 50%，而 PERG 峰值潜伏期增加约 40ms（方差分析，P < 0.05）。相比之下，年轻和年老的对照小鼠的 PERG 具有相似的幅度和峰值潜伏期。在转基因小鼠中，GFAP 染色比对照小鼠更强烈且扩展，并且随年龄增加而增加；在年老的转基因小鼠中，神经丝染色显示轴突肿胀和部分变性。年轻的转基因小鼠的 IOP 与对照小鼠相似，并且随年龄的增加没有显著变化。
表达突变型人类肌球蛋白的转基因小鼠显示出与年龄相关的 RGC 电反应性的进行性变化，这些变化与 IOP 升高无关，但与明显的星形胶质细胞增生和轴突病变有关。我们的结果支持这样的观点，即 MYOC 在视神经中的表达可能会影响 RGC 轴突的结构、代谢或神经营养支持，从而独立于 IOP 影响其对青光眼损伤的易感性。
