Berkowitz Bruce A, Grady Edmund Michael, Roberts Robin
Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit, MI, USA; Department of Ophthalmology, Wayne State University School of Medicine, Detroit, MI, USA.
Department of Ophthalmology, Wayne State University School of Medicine, Detroit, MI, USA.
Neurobiol Aging. 2014 Aug;35(8):1883-91. doi: 10.1016/j.neurobiolaging.2014.02.020. Epub 2014 Mar 2.
Prior work in healthy rats supported a calcium hypothesis of photoreceptor aging, wherein progressive age-related declines in photopic vision are explainable by the extent of earlier escalating d-cis-diltiazem-insensitive increases in photoreceptor L-type calcium channel (LTCC) activity in vivo. Unlike rats, healthy mice have relatively stable photopic vision until after 18 months of age. We therefore hypothesized that photoreceptor LTCC activity in mice would not progressively increase until after 18 months. In 2-5, 10, 18, and 26 months male C57Bl/6J mice, photoreceptor LTCC activity and retinal thickness were evaluated in vivo (manganese-enhanced magnetic resonance imaging) with some groups also treated with d-cis-diltiazem; visual performance was evaluated (optokinetic tracking). Data were calibrated for cone-only responses using mice without rod transducin (GNAT1-/-). Photopic vision was stable until after 18 months without retinal thinning or progressive increases in retinal manganese uptake. We measured an uptake spike at 10 months. This spike, unlike that in the rat, was diltiazem sensitive in the dark and diltiazem insensitive in the light. Between dark and light, uptake in inner retina of older mice was unequal (unlike that in 2-5 months mice); outer retinal uptake was similar to that in 2-5 months mice. Stable murine photopic visual performance and nonescalating photoreceptor LTCC activity before 18 months of age were consistent with a prediction of the calcium hypothesis. Stark differences in the temporal evolution of mouse and rat photoreceptor LTCC activity suggest the need for personalized identification of the retinal mechanisms contributing to declines in photopic vision to ensure success of future treatment efforts.
先前在健康大鼠身上开展的研究支持了光感受器衰老的钙假说，即与年龄相关的明视觉逐渐下降可通过体内光感受器L型钙通道（LTCC）活性早期不断上升且对d-顺式地尔硫䓬不敏感的程度来解释。与大鼠不同，健康小鼠在18个月龄之前明视觉相对稳定。因此，我们推测小鼠光感受器LTCC活性在18个月龄之后才会逐渐增加。在2至5个月、10个月、18个月和26个月大的雄性C57Bl/6J小鼠中，通过体内锰增强磁共振成像评估光感受器LTCC活性和视网膜厚度，部分组还用d-顺式地尔硫䓬进行了处理；通过视动跟踪评估视觉表现。使用没有视杆转导蛋白的小鼠（GNAT1-/-）对仅视锥细胞反应的数据进行校准。明视觉在18个月龄之前保持稳定，视网膜没有变薄，视网膜锰摄取也没有逐渐增加。我们在10个月时测量到一个摄取峰值。与大鼠不同，这个峰值在黑暗中对地尔硫䓬敏感，在光照下对地尔硫䓬不敏感。在黑暗和光照条件下，老年小鼠内视网膜的摄取不均等（与2至5个月大的小鼠不同）；外视网膜摄取与2至5个月大的小鼠相似。18个月龄之前小鼠稳定的明视觉表现和光感受器LTCC活性不增加与钙假说的预测一致。小鼠和大鼠光感受器LTCC活性的时间演变存在明显差异，这表明需要针对导致明视觉下降的视网膜机制进行个性化识别，以确保未来治疗努力取得成功。
