期刊
NATURE
卷 493, 期 7432, 页码 371-U113出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature11628
关键词
-
资金
- Canadian Institutes of Health Research [MOP-114994, MOP-10848, MOP-93679, MOP-44050]
- Autism Speaks [7109]
- Fonds de la Recherche en Sante du Quebec (FRSQ
- Groupe de Recherche sur le Systeme Nerveux Central)
- National Institutes of Health [NIH RO1 CA154916, NIH RO1 CA140456]
- Canada Research Chair in Cellular and Molecular Neurophysiology
- Savoy Foundation
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据