Autism-related deficits via dysregulated eIF4E-dependent translational control

Christos G. Gkogkas, Arkady Khoutorsky, Israeli Ran, Emmanouil Rampakakis, Tatiana Nevarko, Daniel B. Weatherill, Cristina Vasuta, Stephanie Yee, Morgan Truitt, Paul Dallaire, François Major, Paul Lasko, Davide Ruggero, Karim Nader, Jean-Claude Lacaille () and Nahum Sonenberg ()
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Christos G. Gkogkas: McGill University, Montreal, Quebec H3A 1A3, Canada
Arkady Khoutorsky: McGill University, Montreal, Quebec H3A 1A3, Canada
Israeli Ran: Université de Montréal, Montreal, Quebec H3C 3J7, Canada
Emmanouil Rampakakis: McGill University, Montreal, Quebec H3A 1A3, Canada
Tatiana Nevarko: McGill University, Montreal, Quebec H3A 1A3, Canada
Daniel B. Weatherill: Université de Montréal, Montreal, Quebec H3C 3J7, Canada
Cristina Vasuta: Université de Montréal, Montreal, Quebec H3C 3J7, Canada
Stephanie Yee: McGill University, Montreal, Quebec H3G 0B1, Canada
Morgan Truitt: Helen Diller Family Comprehensive Cancer Center, University of California
Paul Dallaire: Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec H3C 3J7, Canada
François Major: Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec H3C 3J7, Canada
Paul Lasko: McGill University, Montreal, Quebec H3G 0B1, Canada
Davide Ruggero: Helen Diller Family Comprehensive Cancer Center, University of California
Karim Nader: McGill University, Montreal, Quebec H3A 1B1, Canada
Jean-Claude Lacaille: Université de Montréal, Montreal, Quebec H3C 3J7, Canada
Nahum Sonenberg: McGill University, Montreal, Quebec H3A 1A3, Canada

Nature, 2013, vol. 493, issue 7432, 371-377

Abstract: Abstract 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.

Date: 2013
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DOI: 10.1038/nature11628

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