Reduced synaptic vesicle density and aberrant synaptic localization caused by a splice site mutation in the Rs1h gene
Reduced synaptic vesicle density and aberrant synaptic localization caused by a splice site mutation in the Rs1h gene
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DOI：
10.1017/s0952523806230244
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发表时间：
2006-11-01
影响因子：
1.9
通讯作者：
Ikeda, Akihiro
中科院分区：
文献类型：
--
作者：
Johnson, Britt A.;Ikeda, Sakae;Ikeda, Akihiro
X连锁视网膜劈裂症(XLRS)是一种常见的遗传性黄斑变性，由RS1基因突变引起。虽然RS1在视网膜的突触结构和层组织中的作用已经被涉及，但RS1基因缺陷对光感受器细胞和二级神经元之间突触相互作用的病理影响还没有得到深入的研究。在这项研究中，我们对小鼠RS1同源基因(Rs1h(Tmgc1))剪接位点突变引起的视网膜突触表型进行了详细的表征。电子显微镜分析表明，光感受器细胞的突触前终末在Rs1h(Tmgc1)视网膜内含有较低的突触小泡的面密度。对外丛状层突触相互作用的研究还发现，光感受器细胞突触前标记的异位定位和突触后神经元(双极细胞和水平细胞)的轴突延长，这在其他光感受器细胞分子缺陷的小鼠模型中也观察到。与这些突触异常相一致的是，对年轻的Rs1h(Tmgc1)小鼠的ERG分析显示，b波的衰减而a波的保留。这些结果表明，RS1H在光感受器和二级神经元之间的突触的形态和功能上具有功能意义。从出生后第15天到第19天的发育研究表明，突触相互作用形成正常，突触形成完成后出现结构异常，表明RS1H对这种突触相互作用的维持是重要的。因此，Rs1h(Tmgc1)小鼠可能成为人类XLRS和其他突触疾病的新的遗传模型。
X-linked retinoschisis (XLRS) is a common form of inherited macular degeneration caused by mutations in the RS1 gene. Whereas the role of RS1 has been implicated in the synaptic structure as well as layer organization in the retina, the pathological effect of a defective RS1 gene on the synaptic interaction between photoreceptor cells and second-order neurons has not been thoroughly investigated. In this study, we perform a detailed characterization of the retina] synaptic phenotypes caused by a splice site mutation in the murine RS1 homolog (Rs1h(tmgc1)). Electron microscopic analysis showed that presynaptic terminals of photoreceptor cells contain a lower areal density of synaptic vesicles in the Rs1h(tmgc1) retina. Examination of the synaptic interactions in the outer plexiform layer also revealed ectopic localization of photoreceptor cell presynaptic markers and elongation of neurites from postsynaptic neurons (bipolar and horizontal cells), which are observed in other mouse models with defective photoreceptor cell molecules. Consistent with these synaptic abnormalities, ERG analysis of young Rs1h(tmgc1) mice revealed attenuation of the b-wave with preservation of the a-wave. These results demonstrate that RS1H has functional significance in the morphology and function of the synapse between photoreceptors and second-order neurons. A developmental study from postnatal day (P) 15 through P19 showed that synaptic interactions form normally, and structural abnormalities occur after completion of synaptic formation suggesting that RS1H is important for the maintenance of this synaptic interaction. Thus, Rs1h(tmgc1) mice may serve as a new genetic model for human XLRS and other synaptic disorders.