Neurons generated by direct conversion of fibroblasts reproduce synaptic phenotype caused by autism-associated neuroligin-3 mutation
Neurons generated by direct conversion of fibroblasts reproduce synaptic phenotype caused by autism-associated neuroligin-3 mutation
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DOI：
10.1073/pnas.1316240110
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发表时间：
2013-10-08
影响因子：
11.1
通讯作者：
Suedhof, Thomas C.
中科院分区：
文献类型：
--
作者：
Chanda, Soham;Marro, Samuele;Suedhof, Thomas C.
最近的研究表明，从非神经细胞直接转分化而来的诱导神经元(IN)细胞为研究神经精神疾病提供了一个强大的机会。然而，使用这种方法来检查疾病特异性变化的有效性还没有得到证明。在这里，我们分析了从携带神经连接蛋白-3中与自闭症相关的R704C替换的小鼠的野生型和突变小鼠的小鼠胚胎成纤维细胞中获得的IN细胞的表型。我们发现，细胞中的神经连接蛋白-3R704C突变体对AMPA型谷氨酸受体介导的突触传递有较大的选择性降低，而对NMDA型谷氨酸受体或GABAA受体介导的突触传递没有影响。因此，在细胞中观察到的R704C突变的突触表型复制了先前观察到的R704C突变神经元的表型。我们的数据表明，R704C突变的影响甚至适用于从成纤维细胞转分化的神经元，并构成了一个概念验证证明，在细胞中可以用于细胞疾病建模。
Recent studies suggest that induced neuronal (iN) cells that are directly transdifferentiated from nonneuronal cells provide a powerful opportunity to examine neuropsychiatric diseases. However, the validity of using this approach to examine disease-specific changes has not been demonstrated. Here, we analyze the phenotypes of iN cells that were derived from murine embryonic fibroblasts cultured from littermate wild-type and mutant mice carrying the autism-associated R704C substitution in neuroligin-3. We show that neuroligin-3 R704C-mutant iN cells exhibit a large and selective decrease in AMPA-type glutamate receptor-mediated synaptic transmission without changes in NMDA-type glutamate receptor-or in GABAA receptor-mediated synaptic transmission. Thus, the synaptic phenotype observed in R704C-mutant iN cells replicates the previously observed phenotype of R704C-mutant neurons. Our data show that the effect of the R704C mutation is applicable even to neurons transdifferentiated from fibroblasts and constitute a proof-of-concept demonstration that iN cells can be used for cellular disease modeling.