The regulation of protein synthesis is a critical step in gene expression, and its dysfunction is implicated in autism spectrum disorder (ASD). The eIF4E homologous protein (4EHP, also termed eIF4E2) binds to the mRNA 5′ cap to repress translation. The stability of 4EHP is maintained through physical interaction with GRB10 interacting GYF protein 2 (GIGYF2). Gene-disruptive mutations in GIGYF2 are linked to ASD, but causality is lacking. We hypothesized that GIGYF2 mutations cause ASD by disrupting 4EHP function. Since homozygous deletion of either gene is lethal, we generated a cell-type-specific knockout model where Eif4e2 (the gene encoding 4EHP) is deleted in excitatory neurons of the forebrain (4EHP-eKO). In this model, we investigated ASD-associated synaptic plasticity dysfunction, ASD-like behaviors, and global translational control. We also utilized mice lacking one copy of Gigyf2, Eif4e2 or co-deletion of one copy of each gene to further investigate ASD-like behaviors. 4EHP is expressed in excitatory neurons and synaptosomes, and its amount increases during development. 4EHP-eKO mice display exaggerated mGluR-LTD, a phenotype frequently observed in mouse models of ASD. Consistent with synaptic plasticity dysfunction, the mice displayed social behavior impairments without being confounded by deficits in olfaction, anxiety, locomotion, or motor ability. Repetitive behaviors and vocal communication were not affected by loss of 4EHP in excitatory neurons. Heterozygous deletion of either Gigyf2, Eif4e2, or both genes in mice did not result in ASD-like behaviors (i.e. decreases in social behavior or increases in marble burying). Interestingly, exaggerated mGluR-LTD and impaired social behaviors were not attributed to changes in hippocampal global protein synthesis, which suggests that 4EHP and GIGYF2 regulate the translation of specific mRNAs to mediate these effects. This study did not identify which genes are translationally regulated by 4EHP and GIGYF2. Identification of mistranslated genes in 4EHP-eKO mice might provide a mechanistic explanation for the observed impairment in social behavior and exaggerated LTD. Future experiments employing affinity purification of translating ribosomes and mRNA sequencing in 4EHP-eKO mice will address this relevant issue. Together these results demonstrate an important role of 4EHP in regulating hippocampal plasticity and ASD-associated social behaviors, consistent with the link between mutations in GIGYF2 and ASD.

中文翻译：

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eIF4E 同源物 4EHP (eIF4E2) 调节海马长期抑郁并影响社会行为

蛋白质合成的调节是基因表达的关键步骤，其功能障碍与自闭症谱系障碍（ASD）有关。eIF4E 同源蛋白（4EHP，也称为 eIF4E2）与 mRNA 5'帽结合以抑制翻译。4EHP 的稳定性是通过与 GRB10 相互作用 GYF 蛋白 2 (GIGYF2) 的物理相互作用来维持的。GIGYF2 中的基因破坏性突变与 ASD 相关，但缺乏因果关系。我们假设 GIGYF2 突变通过破坏 4EHP 功能导致 ASD。由于任一基因的纯合缺失是致命的，我们生成了一个细胞类型特异性敲除模型，其中 Eif4e2（编码 4EHP 的基因）在前脑兴奋性神经元 (4EHP-eKO) 中被删除。在这个模型中，我们研究了 ASD 相关的突触可塑性功能障碍、ASD 样行为和全局平移控制。我们还利用缺少一份 Gigyf2、Eif4e2 或每个基因的一份拷贝的共同缺失的小鼠来进一步研究 ASD 样行为。4EHP 在兴奋性神经元和突触体中表达，其数量在发育过程中增加。4EHP-eKO 小鼠表现出夸张的 mGluR-LTD，这是 ASD 小鼠模型中经常观察到的一种表型。与突触可塑性功能障碍一致，小鼠表现出社交行为障碍，而不会被嗅觉、焦虑、运动或运动能力的缺陷所混淆。重复行为和声音交流不受兴奋性神经元中 4EHP 损失的影响。小鼠中 Gigyf2、Eif4e2 或这两个基因的杂合缺失不会导致 ASD 样行为（即社会行为减少或大理石埋葬增加）。有趣的是，夸大的 mGluR-LTD 和受损的社会行为并非归因于海马全局蛋白合成的变化，这表明 4EHP 和 GIGYF2 调节特定 mRNA 的翻译以介导这些影响。这项研究没有确定哪些基因受 4EHP 和 GIGYF2 的翻译调控。4EHP-eKO 小鼠中错误翻译基因的鉴定可能为观察到的社会行为障碍和夸大的 LTD 提供机械解释。未来在 4EHP-eKO 小鼠中采用亲和纯化翻译核糖体和 mRNA 测序的实验将解决这一相关问题。这些结果共同证明了 4EHP 在调节海马可塑性和 ASD 相关社会行为方面的重要作用，这与 GIGYF2 和 ASD 突变之间的联系一致。