Loss of circadian photoentrainment and abnormal retinal electrophysiology in Math5 mutant mice
Loss of circadian photoentrainment and abnormal retinal electrophysiology in Math5 mutant mice
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DOI：
10.1167/iovs.04-1123
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发表时间：
2005-07-01
影响因子：
4.4
通讯作者：
Glaser, T
中科院分区：
文献类型：
--
作者：
Brzezinski, JA;Brown, NL;Glaser, T
目的.研究Math 5（Atoh 7）突变小鼠视网膜神经节细胞（RGCs）缺失对昼夜节律行为和视网膜功能的影响。在各种光暗循环条件下测量野生型和Math 5突变小鼠的轮跑行为。为了从解剖学上评估视交叉上核（SCN）的视网膜输入，在体内标记了视网膜下丘脑束。为了评估视网膜功能的变化，在黑暗和光适应条件下比较了突变型和野生型小鼠的角膜闪光视网膜电图（ERG）。视网膜神经元群体的改变进行了定量评估，并与细胞类型特异性标记。Math 5基因敲除小鼠不受光照的影响，表现出自由活动的昼夜节律行为，平均周期（23.6 +/- 0.15小时）与野生型小鼠（23.4 +/- 0.19小时）无法区分。辣根过氧化物酶结合霍乱毒素B（CT-HRP）示踪剂未显示SCN的顺行标记。从突变小鼠记录的ERG具有减少的暗视a波和b波以及明视b波振幅。暗视b波比a波受影响更严重。振荡电位（OPs）和暗视阈值反应（STR）也降低。与这些ERG结果一致，突变小鼠双极细胞数量的泛特异性减少和杆细胞数量的较小相对减少。Math 5缺失小鼠是钟盲的，并且没有RGC向SCN的投射。因此，RGC对于小鼠中的光夹带是必需的，但对于SCN时钟的发育或内在功能不是必需的。RGC不需要在小鼠中产生任何主要的ERG波形，包括STR，其由一些其他物种的神经节细胞产生。Math 5突变体中b波、OP和STR成分的振幅减小最有可能是由视网膜中间神经元丰度降低引起的。
Purpose. To determine how the absence of retinal ganglion cells (RGCs) in Math5 (Atoh7) mutant mice affects circadian behavior and retinal function.Methods. The wheel-running behavior of wild-type and Math5 mutant mice was measured under various light-dark cycle conditions. To evaluate retinal input to the suprachiasmatic nuclei (SCN) anatomically, the retinohypothalamic tracts were labeled in vivo. To assess changes in retinal function, corneal flash electroretinograms (ERGs) from mutant and wild-type mice were compared under dark- and light-adapted conditions. Alterations in retinal neuron populations were evaluated quantitatively and with cell-type-specific markers.Results. The Math5-null mice did not entrain to light and exhibited free-running circadian behavior with a mean period (23.6 +/- 0.15 hours) that was indistinguishable from that of wild-type mice (23.4 +/- 0.19 hours). The SCN showed no anterograde labeling with a horseradish peroxidase-conjugated cholera toxin B (CT-HRP) tracer. ERGs recorded from mutant mice had diminished scotopic a- and b-wave and photopic b-wave amplitudes. The scotopic b-wave was more severely affected than the a- wave. The oscillatory potentials (OPs) and scotopic threshold response (STR) were also reduced. Consistent with these ERG findings, a pan-specific reduction in the number of bipolar cells and a smaller relative decrease in the number of rods in mutant mice were observed.Conclusions. Math5-null mice are clock-blind and have no RGC projections to the SCN. RGCs are thus essential for photoentrainment in mice, but are not necessary for the development or intrinsic function of the SCN clock. RGCs are not required to generate any of the major ERG waveforms in mice, including the STR, which is produced by ganglion cells in some other species. The diminished amplitude of b-wave, OPs, and STR components in Math5 mutants is most likely caused by the decreased abundance of retinal interneurons.