Liu Xiaoni, Kerov Vasily, Haeseleer Françoise, Majumder Anurima, Artemyev Nikolai, Baker Sheila A, Lee Amy
Department of Molecular Physiology and Biophysics; University of Iowa; Iowa City, IA USA; Departments of Otolaryngology-Head and Neck Surgery, and Neurology; University of Iowa; Iowa City, IA USA.
Department of Molecular Physiology and Biophysics; University of Iowa; Iowa City, IA USA; Departments of Otolaryngology-Head and Neck Surgery, and Neurology; University of Iowa; Iowa City, IA USA; Department of Biochemistry; University of Iowa; Iowa City, IA USA.
Channels (Austin). 2013 Nov-Dec;7(6):514-23. doi: 10.4161/chan.26376. Epub 2013 Sep 24.
Mutations in the gene encoding Cav 1.4, CACNA1F, are associated with visual disorders including X-linked incomplete congenital stationary night blindness type 2 (CSNB2). In mice lacking Cav 1.4 channels, there are defects in the development of "ribbon" synapses formed between photoreceptors (PRs) and second-order neurons. However, many CSNB2 mutations disrupt the function rather than expression of Cav 1.4 channels. Whether defects in PR synapse development due to altered Cav 1.4 function are common features contributing to the pathogenesis of CSNB2 is unknown. To resolve this issue, we profiled changes in the subcellular distribution of Cav 1.4 channels and synapse morphology during development in wild-type (WT) mice and mouse models of CSNB2. Using Cav 1.4-selective antibodies, we found that Cav 1.4 channels associate with ribbon precursors early in development and are concentrated at both rod and cone PR synapses in the mature retina. In mouse models of CSNB2 in which the voltage-dependence of Cav 1.4 activation is either enhanced (Cav 1.4I756T) or inhibited (CaBP4 KO), the initial stages of PR synaptic ribbon formation are largely unaffected. However, after postnatal day 13, many PR ribbons retain the immature morphology. This synaptic abnormality corresponds in severity to the defect in synaptic transmission in the adult mutant mice, suggesting that lack of sufficient mature synapses contributes to vision impairment in Cav 1.4I756T and CaBP4 KO mice. Our results demonstrate the importance of proper Cav 1.4 function for efficient PR synapse maturation, and that dysregulation of Cav 1.4 channels in CSNB2 may have synaptopathic consequences.
编码Cav 1.4（CACNA1F）的基因突变与包括X连锁不完全先天性静止性夜盲2型（CSNB2）在内的视觉障碍有关。在缺乏Cav 1.4通道的小鼠中，光感受器（PR）与二级神经元之间形成的“带状”突触的发育存在缺陷。然而，许多CSNB2突变破坏了Cav 1.4通道的功能而非表达。由于Cav 1.4功能改变导致的PR突触发育缺陷是否是导致CSNB2发病机制的共同特征尚不清楚。为了解决这个问题，我们分析了野生型（WT）小鼠和CSNB2小鼠模型发育过程中Cav 1.4通道亚细胞分布和突触形态的变化。使用Cav 1.4选择性抗体，我们发现Cav 1.4通道在发育早期与带状前体相关，并集中在成熟视网膜的视杆和视锥PR突触处。在Cav 1.4激活的电压依赖性增强（Cav 1.4I756T）或受到抑制（CaBP4基因敲除）的CSNB2小鼠模型中，PR突触带状物形成的初始阶段基本不受影响。然而，在出生后第13天之后，许多PR带状物保留了未成熟的形态。这种突触异常的严重程度与成年突变小鼠突触传递缺陷相对应，表明缺乏足够的成熟突触导致了Cav 1.4I756T和CaBP4基因敲除小鼠的视力受损。我们的结果证明了适当的Cav 1.4功能对于有效的PR突触成熟的重要性，并且CSNB2中Cav 1.4通道的失调可能具有突触病变的后果。
