α2δ-4 Is Required for the Molecular and Structural Organization of Rod and Cone Photoreceptor Synapses
α2δ-4 Is Required for the Molecular and Structural Organization of Rod and Cone Photoreceptor Synapses
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DOI：
10.1523/jneurosci.3818-16.2018
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发表时间：
2018-07-04
影响因子：
5.3
通讯作者：
Lee, Amy
中科院分区：
文献类型：
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作者：
Kerov, Vasily;Laird, Joseph G.;Lee, Amy
α（2）δ-4是电压门控Ca（v）1.4 L型通道的辅助亚基，其调节光感受器带状突触的发育和成熟胞吐功能。在人类中，编码α（2）δ-4的CACNA 2D 4基因的突变导致人类不同形式的视力损害，其潜在的致病机制仍不清楚。为了研究alpha（2）delta-4的视网膜功能，我们使用基因组编辑来产生alpha（2）delta-4敲除（alpha（2）delta-4 KO）小鼠。在雄性和雌性α（2）δ-4基因敲除小鼠中，杆小球在发育早期缺乏带状物和其他突触标志。虽然锥突触的分子组织比杆突触受影响小，但在α（2）δ-4 KO视网膜中，水平和锥双极突起在外核层中异常延伸。在重建的α（2）δ-4 KO锥椎弓根的连续块面扫描电子显微镜，丝带似乎正常，除了不到三分之一的显示预期的三联组织的过程在带状网站。α 2 δ 4基因敲除小鼠中突触缺陷的严重程度与Ca（v）1.4通道的进行性丧失相关，首先是在视杆细胞末端，随后是视锥细胞。尽管在视网膜电图中没有b波，但视觉引导行为在alpha（2）delta-4 KO小鼠中是明显的，并且在明视条件下比暗视条件下更好。我们的结论是，α（2）δ-4在维持视杆和视锥突触的结构和功能完整性方面起着至关重要的作用，其破坏可能导致CACNA 2D 4突变的人类视力障碍。
alpha(2)delta-4 is an auxiliary subunit of voltage-gated Ca(v)1.4 L-type channels that regulate the development and mature exocytotic function of the photoreceptor ribbon synapse. In humans, mutations in the CACNA2D4 gene encoding alpha(2)delta-4 cause heterogeneous forms of vision impairment in humans, the underlying pathogenic mechanisms of which remain unclear. To investigate the retinal function of alpha(2)delta-4, we used genome editing to generate an alpha(2)delta-4 knock-out (alpha(2)delta-4 KO) mouse. In male and female alpha(2)delta-4 KO mice, rod spherules lack ribbons and other synaptic hallmarks early in development. Although the molecular organization of cone synapses is less affected than rod synapses, horizontal and cone bipolar processes extend abnormally in the outer nuclear layer in alpha(2)delta-4 KO retina. In reconstructions of alpha(2)delta-4 KO cone pedicles by serial block face scanning electron microscopy, ribbons appear normal, except that less than one-third show the expected triadic organization of processes at ribbon sites. The severity of the synaptic defects in alpha(2)delta-4 KO mice correlates with a progressive loss of Ca(v)1.4 channels, first in terminals of rods and later cones. Despite the absence of b-waves in electroretinograms, visually guided behavior is evident in alpha(2)delta-4 KO mice and better under photopic than scotopic conditions. We conclude that alpha(2)delta-4 plays an essential role in maintaining the structural and functional integrity of rod and cone synapses, the disruption of which may contribute to visual impairment in humans with CACNA2D4 mutations.