title: Inhibition of Group I Metabotropic Glutamate Receptors Reverses Autistic-Like Phenotypes Caused by Deficiency of the Translation Repressor eIF4E Binding Protein 2.
abstract: Exacerbated mRNA translation during brain development has been linked to autism spectrum disorders (ASDs). Deletion of the eukaryotic initiation factor 4E (eIF4E)-binding protein 2 gene (Eif4ebp2), encoding the suppressor of mRNA translation initiation 4E-BP2, leads to an imbalance in excitatory-to-inhibitory neurotransmission and ASD-like behaviors. Inhibition of group I metabotropic glutamate receptors (mGluRs) mGluR1 and mGluR5 reverses the autistic phenotypes in several ASD mouse models. Importantly, these receptors control synaptic physiology via activation of mRNA translation. We investigated the potential reversal of autistic-like phenotypes in Eif4ebp2(-/-) mice by using antagonists of mGluR1 (JNJ16259685) or mGluR5 (fenobam). Augmented hippocampal mGluR-induced long-term depression (LTD; or chemically induced mGluR-LTD) in Eif4ebp2(-/-) mice was rescued by mGluR1 or mGluR5 antagonists. While rescue by mGluR5 inhibition occurs through the blockade of a protein synthesis-dependent component of LTD, normalization by mGluR1 antagonists requires the activation of protein synthesis. Synaptically induced LTD was deficient in Eif4ebp2(-/-) mice, and this deficit was not rescued by group I mGluR antagonists. Furthermore, a single dose of mGluR1 (0.3 mg/kg) or mGluR5 (3 mg/kg) antagonists in vivo reversed the deficits in social interaction and repetitive behaviors (marble burying) in Eif4ebp2(-/-) mice. Our results demonstrate that Eif4ebp2(-/-) mice serve as a relevant model to test potential therapies for ASD symptoms. In addition, we provide substantive evidence that the inhibition of mGluR1/mGluR5 is an effective treatment for physiological and behavioral alterations caused by exacerbated mRNA translation initiation.
  
  
  CONCLUSIONS
  Exacerbated mRNA translation during brain development is associated with several autism spectrum disorders (ASDs). We recently demonstrated that the deletion of a negative regulator of mRNA translation initiation, the eukaryotic initiation factor 4E-binding protein 2, leads to ASD-like behaviors and increased excitatory synaptic activity. Here we demonstrated that autistic behavioral and electrophysiological phenotypes can be treated in adult mice with antagonists of group I metabotropic glutamate receptors (mGluRs), which have been previously used in other ASD models (i.e., fragile X syndrome). These findings support the use of group I mGluR antagonists as a potential therapy that extends to autism models involving exacerbated mRNA translation initiation.
authors.affiliation: Department of Neurosciences and Groupe de Recherche sur le Système Nerveux Central, Université de Montréal, Montréal, Québec H3C 3J7, Canada, Department of Biochemistry and Goodman Cancer Centre, McGill University, Montréal, Québec H3A 1A3, Canada.
authors.forename: Argel
authors.initials: A
authors.lastname: Aguilar-Valles
authors.affiliation: Department of Biochemistry and Goodman Cancer Centre, McGill University, Montréal, Québec H3A 1A3, Canada.
authors.forename: Edna
authors.initials: E
authors.lastname: Matta-Camacho
authors.affiliation: Department of Biochemistry and Goodman Cancer Centre, McGill University, Montréal, Québec H3A 1A3, Canada.
authors.forename: Arkady
authors.identifier: http://orcid.org/0000-0002-0457-9860
authors.initials: A
authors.lastname: Khoutorsky
authors.affiliation: Department of Biochemistry and Goodman Cancer Centre, McGill University, Montréal, Québec H3A 1A3, Canada, Patrick Wild Centre and Centre for Integrative Physiology, University of Edinburgh, Edinburgh EH8 9XD, United Kingdom.
authors.forename: Christos
authors.identifier: http://orcid.org/0000-0001-6281-3419
authors.initials: C
authors.lastname: Gkogkas
authors.affiliation: Department of Psychology, McGill University, Montréal, Québec H3A 1B1, Canada, and.
authors.forename: Karim
authors.initials: K
authors.lastname: Nader
authors.affiliation: Department of Neurosciences and Groupe de Recherche sur le Système Nerveux Central, Université de Montréal, Montréal, Québec H3C 3J7, Canada, jean-claude.lacaille@umontreal.ca nahum.sonenberg@mcgill.ca.
authors.forename: Jean-Claude
authors.identifier: http://orcid.org/0000-0003-4056-0574
authors.initials: JC
authors.lastname: Lacaille
authors.affiliation: Department of Biochemistry and Goodman Cancer Centre, McGill University, Montréal, Québec H3A 1A3, Canada, jean-claude.lacaille@umontreal.ca nahum.sonenberg@mcgill.ca.
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D039642:Eukaryotic Initiation Factors / Q000235:genetics / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011804:Quinolines / Q000494:pharmacology; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D012919:Social Behavior; D013239:Stereotyped Behavior
chemical_list: C495417:(3,4-dihydro-2H-pyrano(2,3)b-quinolin-7-yl)-(cis-4-methoxycyclohexyl) methanone; C491255:Eif4ebp2 protein, mouse; D039642:Eukaryotic Initiation Factors; D018691:Excitatory Amino Acid Antagonists; D007093:Imidazoles; D011804:Quinolines; D018094:Receptors, Metabotropic Glutamate; C032794:fenobam
keywords: autism spectrum disorders; group I mGluRs; long-term depression; repetitive behavior; social interaction; translation initiation