Electrophysiological and Histologic Assessment of Retinal Ganglion Cell Fate in a Mouse Model for OPA1-Associated Autosomal Dominant Optic Atrophy
Electrophysiological and Histologic Assessment of Retinal Ganglion Cell Fate in a Mouse Model for OPA1-Associated Autosomal Dominant Optic Atrophy
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DOI：
10.1167/iovs.09-3606
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发表时间：
2010-03-01
影响因子：
4.4
通讯作者：
Alavi, Marcel V.
中科院分区：
文献类型：
--
作者：
Heiduschka, Peter;Schnichels, Sven;Alavi, Marcel V.
目的。常染色体显性视神经萎缩（ADOA）的主要疾病特征是双侧视力下降、盲肠中央暗点和经常出现的三盲，这归因于视网膜神经节细胞（RGC）的进行性丧失和随后的视神经变性。主要致病基因是OPA1。在这里，我们通过电生理测量检查携带 Opa1 致病性突变的小鼠，并评估 RGC 的命运。方法。两岁的动物通过视网膜电图（ERG）和视觉诱发电位（VEP）测量进行全面检查，以评估外视网膜、内视网膜和视神经的功能。进行逆行荧光金标记以确定存活的 RGC 数量并通过神经丝复染评估轴突运输。通过 Iba-1 染色鉴定吞噬作用依赖性标记小胶质细胞。结果。老年 Opa1 小鼠的 ERG 反应正常。 VEP 测量显示振幅显着降低，但与青光眼中发现的延长潜伏期相比，潜伏期没有变化。 RGC 的逆行标记显示 Opa1 小鼠中 RGC 的数量显着减少。长期实验揭示了摄入荧光染料的小胶质细胞的存在。结论。这是老年 Opa1 小鼠视觉功能缺陷的首次电生理学证明。 VEP 测量和逆行标记实验表明 RGC 数量减少，而其余 RGC 和轴突功能正常。总而言之，这些发现支持从体体到轴突的退化过程呈上升趋势。 （投资眼科可见科学。2010 年；51：1424-1431）DOI：10.1167/iovs.09-3606
PURPOSE. The main disease features of autosomal dominant optic atrophy (ADOA) are a bilateral reduction of visual acuity, cecocentral scotoma, and frequently tritanopia, which have been ascribed to a progressive loss of retinal ganglion cells (RGCs) and subsequent degeneration of the optic nerve. The main disease-causing gene is OPA1. Here, we examine a mouse carrying a pathogenic mutation in Opa1 by electrophysiological measurements and assess the fate of RGCs.METHODS. Two-year-old animals underwent a full examination by electroretinography (ERG) and visually evoked potential (VEP) measurements to assess the function of the outer and inner retina and the optic nerve. Retrograde Fluorogold labeling was performed to determine the number of surviving RGCs and to assess axonal transport by neurofilament counterstaining. Phagocytosis-dependent labeled microglial cells were identified by an Iba-1 staining.RESULTS. ERG responses were normal in aged Opa1 mice. VEP measurements revealed significantly reduced amplitudes but no change in the latencies in contrast to extended latencies found in glaucoma. Retrograde labeling of RGCs showed a significant reduction in the number of RGCs in Opa1 mice. Long-term experiments revealed the presence of microglial cells with ingested fluorescent dye.CONCLUSIONS. This is the first electrophysiological demonstration of a visual function deficit in aged Opa1 mice. VEP measurements and retrograde labeling experiments show that the number of RGCs is reduced whereas the remaining RGCs and axons function normally. Taken together, these findings support an ascending progress of degeneration from the soma toward the axon. (Invest Ophthalmol Vis Sci. 2010; 51: 1424-1431) DOI: 10.1167/iovs.09-3606