Late-Onset Inner Retinal Dysfunction in Mice Lacking Sigma Receptor 1 (σR1)
Late-Onset Inner Retinal Dysfunction in Mice Lacking Sigma Receptor 1 (σR1)
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DOI：
10.1167/iovs.11-8169
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发表时间：
2011-09-01
影响因子：
4.4
通讯作者：
Smith, Sylvia B.
中科院分区：
文献类型：
--
作者：
Ha, Yonju;Saul, Alan;Smith, Sylvia B.
目的.σ受体1（σ R1）在眼睛中大量表达，并且一些报道表明这种推定的分子伴侣在透镜细胞存活、眼内压（IOP）控制和视网膜神经保护中起作用。本研究探讨了缺乏sigma R1对眼发育、结构和功能的影响。对5至59周龄的野生型（sigma R1（+/+））、杂合型（sigma R1（+/-））和纯合型（sigma R1（-/-），敲除）小鼠进行全面的电生理学测试和IOP测量。通过光学显微镜和电子显微镜检查眼睛，并进行形态学检查和检测眼球萎缩。sigma R1（-/-）小鼠的角膜和透镜在所有检查年龄的形态学外观方面与野生型小鼠相似，IOP在正常范围内。与野生型小鼠相比，综合ERG和形态测定分析最初在sigma R1（-/-）小鼠中产生了正常的结果。然而，到12个月时，在sigma R1（-/-）小鼠中检测到ERG b波振幅显著降低和负暗视阈值反应减弱，与视网膜内功能障碍一致。伴随这些迟发性变化的是视网膜内层TUNEL和活性半胱天冬酶3阳性细胞的增加以及神经节细胞层细胞的显著损失，特别是在中央视网膜中。在这些功能和结构异常之前，早在6个月大的sigma R1（-/-）小鼠的视神经头中就有轴突破坏的超微结构证据，尽管在sigma R1（-/-）小鼠的视网膜血管化中没有观察到改变。这些数据表明，缺乏sigma R1导致迟发性视网膜功能障碍的发展与视神经病变相似。（Invest Ophthalmol维斯科学。2011;52：7749-7760）DOI：10.1167/iovs.11-8169
PURPOSE. Sigma receptor 1 (sigma R1) is expressed abundantly in the eye, and several reports suggest that this putative molecular chaperone plays a role in lens cell survival, control of intraocular pressure (IOP), and retinal neuroprotection. The present study examined the consequence of the absence of sigma R1 on ocular development, structure, and function.METHODS. Wild-type (sigma R1(+/+)), heterozygous (sigma R1(+/-)), and homozygous (sigma R1(-/-), knockout) mice aged 5 to 59 weeks were subjected to comprehensive electrophysiological testing and IOP measurement. The eyes were examined by light and electron microscopy and subjected to morphometric examination and detection of apoptosis.RESULTS. Cornea and lens of sigma R1(-/-) mice were similar to wild-type mice in morphologic appearance at all ages examined, and IOP was within normal limits. Comprehensive ERG and morphometric analyses initially yielded normal findings in the sigma R1(-/-) mice compared with those in the wild-type. By 12 months, however, significantly decreased ERG b-wave amplitudes and diminished negative scotopic threshold responses, consistent with inner retinal dysfunction, were detected in sigma R1(-/-) mice. Concomitant with these late-onset changes were increased TUNEL- and active caspase 3-positive cells in the inner retina and significant loss of cells in the ganglion cell layer, particularly in the central retina. Before these functional and structural abnormalities, there was ultrastructural evidence of axonal disruption in the optic nerve head of sigma R1(-/-) mice as early as 6 months of age, although there were no alterations observed in retinal vascularization in sigma R1(-/-) mice.CONCLUSIONS. These data suggest that lack of sigma R1 leads to development of late-onset retinal dysfunction with similarities to optic neuropathy. (Invest Ophthalmol Vis Sci. 2011;52:7749-7760) DOI:10.1167/iovs.11-8169