Nuffield Department of Clinical Neurosciences, Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford, United Kingdom.
PLoS One. 2013;8(2):e56350. doi: 10.1371/journal.pone.0056350. Epub 2013 Feb 11.
Autosomal dominant optic atrophy (ADOA) is a slowly progressive optic neuropathy that has been associated with mutations of the OPA1 gene. In patients, the disease primarily affects the retinal ganglion cells (RGCs) and causes optic nerve atrophy and visual loss. A subset of RGCs are intrinsically photosensitive, express the photopigment melanopsin and drive non-image-forming (NIF) visual functions including light driven circadian and sleep behaviours and the pupil light reflex. Given the RGC pathology in ADOA, disruption of NIF functions might be predicted. Interestingly in ADOA patients the pupil light reflex was preserved, although NIF behavioural outputs were not examined. The B6; C3-Opa1(Q285STOP) mouse model of ADOA displays optic nerve abnormalities, RGC dendropathy and functional visual disruption. We performed a comprehensive assessment of light driven NIF functions in this mouse model using wheel running activity monitoring, videotracking and pupillometry. Opa1 mutant mice entrained their activity rhythm to the external light/dark cycle, suppressed their activity in response to acute light exposure at night, generated circadian phase shift responses to 480 nm and 525 nm pulses, demonstrated immobility-defined sleep induction following exposure to a brief light pulse at night and exhibited an intensity dependent pupil light reflex. There were no significant differences in any parameter tested relative to wildtype littermate controls. Furthermore, there was no significant difference in the number of melanopsin-expressing RGCs, cell morphology or melanopsin transcript levels between genotypes. Taken together, these findings suggest the preservation of NIF functions in Opa1 mutants. The results provide support to growing evidence that the melanopsin-expressing RGCs are protected in mitochondrial optic neuropathies.
常染色体显性视神经萎缩（ADOA）是一种进行性缓慢的视神经病变，与 OPA1 基因突变有关。在患者中，该疾病主要影响视网膜神经节细胞（RGC），导致视神经萎缩和视力丧失。RGC 中有一部分是内在光敏的，表达感光色素黑视蛋白，并驱动非成像（NIF）视觉功能，包括光驱动的昼夜节律和睡眠行为以及瞳孔光反射。鉴于 ADOA 中的 RGC 病理学，预计会破坏 NIF 功能。有趣的是，在 ADOA 患者中，瞳孔光反射得以保留，尽管没有检查 NIF 行为输出。B6; C3-Opa1（Q285STOP）ADOA 小鼠模型显示视神经异常、RGC 树突病和功能视觉障碍。我们使用轮式跑步活动监测、视频跟踪和瞳孔计对该小鼠模型中的光驱动 NIF 功能进行了全面评估。Opa1 突变小鼠使它们的活动节律与外部明暗周期同步，在夜间急性光照暴露时抑制其活动，对 480nm 和 525nm 脉冲产生昼夜节律相位移动反应，在夜间短暂光脉冲暴露后表现出不动定义的睡眠诱导，并表现出强度依赖性瞳孔光反射。与野生型同窝对照相比，在任何测试参数上均无显著差异。此外，在基因型之间，黑视蛋白表达的 RGC 数量、细胞形态或黑视蛋白转录水平均无显著差异。综上所述，这些发现表明 Opa1 突变体中 NIF 功能得以保留。这些结果为越来越多的证据提供了支持，即表达黑视蛋白的 RGC 在线粒体视神经病变中受到保护。
