Differential Effects of C1qa Ablation on Glaucomatous Damage in Two Sexes in DBA/2NNia Mice.
Differential Effects of C1qa Ablation on Glaucomatous Damage in Two Sexes in DBA/2NNia Mice.
复制标题
C1qa 消融对 DBA/2NNia 小鼠两种性别青光眼损伤的不同影响。
DOI：
10.1371/journal.pone.0142199
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Danias J
中科院分区：
文献类型：
--
作者：
Kumari R;Astafurov K;Genis A;Danias J
确定C1 qa消融对小鼠脑昏迷性神经变性模型中视网膜神经节细胞（RGC）和视神经（ON）轴突缺失的性别和年龄相关影响。在DBA/2NNia背景下产生同源C1 qa小鼠。雌性和雄性敲除（-/-）、杂合（+/-）和野生型（+/+）小鼠的年龄最大为14个月，并在动物亚组中记录IOP。在用荧光金逆行标记后，将来自所有三个组的5-6、9-10和11-13月龄的小鼠的视网膜平放。由两名独立的观察者以10分制对成像的视网膜进行半定量评分（RGC评分）。视网膜和视神经的子集也用于测量RGC的总数。ON的半薄切片进行成像和分级（ON评分）的轴突损伤的量半定量，由两个蒙面观察员。采用协方差分析（ANCOVA）进行统计学比较。使用5-6月龄C1 qa-/-和C1 qa +/+小鼠的平板视网膜中的小胶质细胞，利用形态学标准评估小胶质细胞活化。与C1 qa +/+动物相比，雌性C1 qa-/-小鼠在8至13月龄之间具有显著更高的IOP（p<0.000001，ANOVA）。在雄性动物中未观察到三种基因型动物之间的IOP差异。在5-6月龄时，两种性别动物的三种基因型之间的RGC或ON评分没有差异。在9-10月龄时，三种基因型之间的雌性小鼠在RGC或ON评分上没有表现出显著差异。然而，与C1 qa +/+小鼠相比，相同年龄的雄性C1 qa-/-和C1 qa +/-小鼠具有更好的RGC和ON评分（对于RGC和ON评分，分别为p<0.003和p<0.05，ANCOVA）。在11-13月龄时，与C1 qa +/+和C1 qa +/-动物相比，雌性C1 qa-/-小鼠具有更好的RGC评分（p<0.006，ANCOVA）。因此，与C1 qa +/+动物相比，C1 qa-/-小鼠具有更高的RGC计数（p<0.03，t检验）。在雄性小鼠中，12个月大的C1 qa-/-动物倾向于具有更好的RGC评分和更高的RGC计数，但这没有达到统计学显著性。11-13月龄动物的ON评分在所有三种基因型之间没有差异。与C1 qa +/+动物相比，雄性5-6月龄C1 qa-/-小鼠的小胶质细胞活化减少;在雌性中未观察到此类效应。C1 qa的缺失改善了DBA/2NNia菌株中的RGC和ON损失，但这种效果在两性之间存在差异。C1 q介导的RGC损伤似乎比IOP介导的RGC损失更有效。相比之下，C1 qa的缺乏提供轴突保护早期，但这种保护不能克服显着的IOP升高的影响。
To determine the sex and age-related effects of C1qa ablation on retinal ganglion cell (RGC) and optic nerve (ON) axonal loss in a mouse model of glaucomatous neurodegeneration. Congenic C1qa mice were generated in the DBA/2NNia background. Female and male knockout (-/-), heterozygous (+/-), and wild type (+/+) mice were aged up to 14 months and IOPs were recorded in a subset of animals. Retinas of mice from all three groups at 5–6, 9–10 and 11–13 months of age were flat-mounted after retrograde labeling with Fluorogold. Imaged retinas were scored (RGC score) semi-quantitatively on a 10 point scale by two independent observers. A subset of retinas and optic nerves were also used for measurement of total number of RGCs. Semi-thin sections of ON were imaged and graded (ON score) for the amount of axonal damage semi-quantitatively, by two masked observers. Analysis of covariance (ANCOVA) was used for statistical comparisons. Microglial cells in flat-mounted retinas of 5–6 month old C1qa -/- and C1qa +/+ mice were used for assessment of microglial activation utilizing morphological criteria. Female C1qa -/- mice had significantly higher IOP (p<0.000001, ANOVA) between 8 and 13 months of age compared to C1qa +/+ animals. No differences in IOPs between animals of the three genotypes were observed in males. At 5–6 months of age, there was no difference in RGC or ON scores between the three genotypes in animals of either sex. At 9–10 months of age, female mice didn’t show significant differences in RGC or ON scores between the three genotypes. However, male C1qa -/- and C1qa +/- mice of the same age had better RGC and ON scores (p<0.003 and p<0.05, ANCOVA, for RGC and ON scores, respectively) compared with C1qa +/+ mice. At 11–13 months of age, female C1qa -/- mice had better RGC scores (p<0.006, ANCOVA) compared to C1qa +/+ and C1qa +/- animals. Accordingly, C1qa -/- mice had higher RGC counts (p<0.03, t-test) compared to C1qa +/+ animals. In male mice, there was a tendency for 12 month old C1qa -/- animals to have better RGC scores and higher RGC counts, but this didn't reach statistical significance. ON scores in 11–13 month old animals of either sex were not different between all three genotype. Microglial activation in male 5–6 month old C1qa -/- mice was decreased compared to C1qa +/+ animals; no such effect was seen in females. Absence of C1qa ameliorates RGC and ON loss in the DBA/2NNia strain, but this effect differs between the two sexes. C1q-mediated RGC damage seems to be more potent than IOP-mediated RGC loss. In contrast, C1qa absence provides axonal protection early on, but this protection cannot overcome the effects of significant IOP elevation.