Autism spectrum disorders (ASDs) are neurodevelopmental disorders with multiple genetic associations. Analysis of de novo mutations identified GRIN2B, which encodes the GluN2B subunit of NMDA receptors, as a gene linked to ASDs with high probability. However, the mechanisms by which GRIN2B mutations contribute to ASD pathophysiology are not understood. Here, we investigated the cellular phenotypes induced by a human mutation that is predicted to truncate GluN2B within the extracellular loop. This mutation abolished NMDA-dependent Ca2+ influx. Mutant GluN2B co-assembled with GluN1 but was not trafficked to the cell surface or dendrites. When mutant GluN2B was expressed in developing cortical neurons, dendrites appeared underdeveloped, with shorter and fewer branches, while spine density was unaffected. Mutant dendritic arbors were often dysmorphic, displaying abnormal filopodial-like structures. Interestingly, dendrite maldevelopment appeared when mutant GluN2B was expressed on a wild-type background, reflecting the disease given that individuals are heterozygous for GRIN2B mutations. Restoring the fourth transmembrane domain and cytoplasmic tail did not rescue the phenotypes. Finally, abnormal development was not accompanied by reduced mTOR signaling. These data suggest that mutations in GluN2B contribute to ASD pathogenesis by disrupting dendrite development.

中文翻译：

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GluN2B中的自闭症相关突变可阻止NMDA受体运输并干扰枝晶生长。

自闭症谱系障碍（ASD）是具有多种遗传关联的神经发育障碍。从头突变的分析确定，编码NMDA受体GluN2B亚基的GRIN2B，是与ASD关联的基因，可能性很高。但是，尚不清楚GRIN2B突变有助于ASD病理生理的机制。在这里，我们调查了人类突变诱导的细胞表型，预计该突变将截断细胞外环内的GluN2B。该突变消除了依赖NMDA的Ca 2+内流。突变体GluN2B与GluN1共组装，但未被贩运到细胞表面或树突中。当突变的GluN2B在发育中的皮质神经元中表达时，树突似乎发育不足，分支越来越短，而脊柱密度却不受影响。突变的树突状乔木经常变形，表现出异常的丝状结构。有趣的是，当突变体GluN2B在野生型背景上表达时，枝晶发育不良，这反映了该疾病，因为个体对于GRIN2B突变是杂合的。恢复第四个跨膜结构域和细胞质尾部不能拯救表型。最后，异常发展并没有伴随着mTOR信号的减少。这些数据表明，GluN2B中的突变通过破坏枝晶发育而促进了ASD发病。最后，异常发展并没有伴随着mTOR信号的减少。这些数据表明，GluN2B中的突变通过破坏枝晶发育而促进了ASD发病。最后，异常发展并没有伴随着mTOR信号的减少。这些数据表明，GluN2B中的突变通过破坏枝晶发育而促进了ASD发病。