Department of Biochemistry & Goodman Cancer Research Centre, McGill University, Montreal, Quebec H3A 1A3, Canada.
Nature. 2013 Jan 17;493(7432):371-7. doi: 10.1038/nature11628. Epub 2012 Nov 21.
Hyperconnectivity of neuronal circuits due to increased synaptic protein synthesis is thought to cause autism spectrum disorders (ASDs). The mammalian target of rapamycin (mTOR) is strongly implicated in ASDs by means of upstream signalling; however, downstream regulatory mechanisms are ill-defined. Here we show that knockout of the eukaryotic translation initiation factor 4E-binding protein 2 (4E-BP2)-an eIF4E repressor downstream of mTOR-or eIF4E overexpression leads to increased translation of neuroligins, which are postsynaptic proteins that are causally linked to ASDs. Mice that have the gene encoding 4E-BP2 (Eif4ebp2) knocked out exhibit an increased ratio of excitatory to inhibitory synaptic inputs and autistic-like behaviours (that is, social interaction deficits, altered communication and repetitive/stereotyped behaviours). Pharmacological inhibition of eIF4E activity or normalization of neuroligin 1, but not neuroligin 2, protein levels restores the normal excitation/inhibition ratio and rectifies the social behaviour deficits. Thus, translational control by eIF4E regulates the synthesis of neuroligins, maintaining the excitation-to-inhibition balance, and its dysregulation engenders ASD-like phenotypes.
神经元回路的超连接性是由于突触蛋白合成增加而引起的，被认为是导致自闭症谱系障碍（ASD）的原因。哺乳动物雷帕霉素靶蛋白（mTOR）通过上游信号强烈暗示与 ASD 有关；然而，下游调节机制尚不清楚。在这里，我们表明，敲除真核翻译起始因子 4E 结合蛋白 2（4E-BP2）——mTOR 下游的 eIF4E 抑制剂，或过表达 eIF4E，会导致神经连接蛋白的翻译增加，而神经连接蛋白是与 ASD 有因果关系的突触后蛋白。缺乏编码 4E-BP2（Eif4ebp2）的基因的小鼠表现出兴奋性突触输入与抑制性突触输入的比例增加，以及类似自闭症的行为（即社交互动缺陷、交流改变和重复/刻板行为）。抑制 eIF4E 活性或使神经连接蛋白 1（而非神经连接蛋白 2）的蛋白水平正常化，可恢复正常的兴奋/抑制比值，并纠正社交行为缺陷。因此，eIF4E 的翻译控制调节神经连接蛋白的合成，维持兴奋与抑制的平衡，其失调会导致类似 ASD 的表型。
