Advertisement

CYFIP1 Dosages Exhibit Divergent Behavioral Impact via Diametric Regulation of NMDA Receptor Complex Translation in Mouse Models of Psychiatric Disorders

  • Author Footnotes
    1 N-SK and FRR contributed equally to this work.
    Nam-Shik Kim
    Footnotes
    1 N-SK and FRR contributed equally to this work.
    Affiliations
    Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
    Search for articles by this author
  • Author Footnotes
    1 N-SK and FRR contributed equally to this work.
    Francisca Rojas Ringeling
    Footnotes
    1 N-SK and FRR contributed equally to this work.
    Affiliations
    Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland

    Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany
    Search for articles by this author
  • Ying Zhou
    Affiliations
    Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland
    Search for articles by this author
  • Ha Nam Nguyen
    Affiliations
    Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland
    Search for articles by this author
  • Stephanie J. Temme
    Affiliations
    Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
    Search for articles by this author
  • Yu-Ting Lin
    Affiliations
    Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland
    Search for articles by this author
  • Stephen Eacker
    Affiliations
    Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland
    Search for articles by this author
  • Valina L. Dawson
    Affiliations
    Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland

    Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland
    Search for articles by this author
  • Ted M. Dawson
    Affiliations
    Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland

    Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland
    Search for articles by this author
  • Bo Xiao
    Affiliations
    Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland
    Search for articles by this author
  • Kuei-sen Hsu
    Affiliations
    Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
    Search for articles by this author
  • Stefan Canzar
    Affiliations
    Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany
    Search for articles by this author
  • Weidong Li
    Affiliations
    Bio-X Institutes, Key Laboratory for the Genetics of Development and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China
    Search for articles by this author
  • Paul Worley
    Affiliations
    Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland
    Search for articles by this author
  • Kimberly M. Christian
    Affiliations
    Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
    Search for articles by this author
  • Ki-Jun Yoon
    Correspondence
    Ki-Jun Yoon, Ph.D.
    Affiliations
    Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
    Search for articles by this author
  • Hongjun Song
    Affiliations
    Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

    Department of Cell and Developmental Biology, Perelman School for Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

    Institute for Regenerative Medicine, Perelman School for Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

    Epigenetics Institute, Perelman School for Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
    Search for articles by this author
  • Guo-li Ming
    Correspondence
    Address correspondence to Guo-li Ming, M.D., Ph.D.
    Affiliations
    Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

    Department of Cell and Developmental Biology, Perelman School for Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

    Institute for Regenerative Medicine, Perelman School for Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

    Department of Psychiatry, Perelman School for Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
    Search for articles by this author
  • Author Footnotes
    1 N-SK and FRR contributed equally to this work.

      Abstract

      Background

      Gene dosage imbalance caused by copy number variations (CNVs) is a prominent contributor to brain disorders. In particular, 15q11.2 CNV duplications and deletions have been associated with autism spectrum disorder and schizophrenia, respectively. The mechanism underlying these diametric contributions remains unclear.

      Methods

      We established both loss-of-function and gain-of-function mouse models of Cyfip1, one of four genes within 15q11.2 CNVs. To assess the functional consequences of altered CYFIP1 levels, we performed systematic investigations on behavioral, electrophysiological, and biochemical phenotypes in both mouse models. In addition, we utilized RNA immunoprecipitation sequencing (RIP-seq) analysis to reveal molecular targets of CYFIP1 in vivo.

      Results

      Cyfip1 loss-of-function and gain-of function mouse models exhibited distinct and shared behavioral abnormalities related to autism spectrum disorder and schizophrenia. RIP-seq analysis identified messenger RNA targets of CYFIP1 in vivo, including postsynaptic NMDA receptor (NMDAR) complex components. In addition, these mouse models showed diametric changes in levels of postsynaptic NMDAR complex components at synapses because of dysregulated protein translation, resulting in bidirectional alteration of NMDAR-mediated signaling. Importantly, pharmacological balancing of NMDAR signaling in these mouse models with diametric Cyfip1 dosages rescues behavioral abnormalities.

      Conclusions

      CYFIP1 regulates protein translation of NMDAR and associated complex components at synapses to maintain normal synaptic functions and behaviors. Our integrated analyses provide insight into how gene dosage imbalance caused by CNVs may contribute to divergent neuropsychiatric disorders.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Geschwind D.H.
        Advances in autism.
        Annu Rev Med. 2009; 60: 367-380
        • Weinberger D.R.
        Implications of normal brain development for the pathogenesis of schizophrenia.
        Arch Gen Psychiatry. 1987; 44: 660-669
        • Malhotra D.
        • Sebat J.
        CNVs: Harbingers of a rare variant revolution in psychiatric genetics.
        Cell. 2012; 148: 1223-1241
        • Carroll L.S.
        • Owen M.J.
        Genetic overlap between autism, schizophrenia and bipolar disorder.
        Genome Med. 2009; 1: 102
        • Crespi B.
        • Stead P.
        • Elliot M.
        Evolution in health and medicine Sackler colloquium: Comparative genomics of autism and schizophrenia.
        Proc Natl Acad Sci U S A. 2010; 107: 1736-1741
        • Kenny E.M.
        • Cormican P.
        • Furlong S.
        • Heron E.
        • Kenny G.
        • Fahey C.
        • et al.
        Excess of rare novel loss-of-function variants in synaptic genes in schizophrenia and autism spectrum disorders.
        Mol Psychiatry. 2014; 19: 872-879
        • Kushima I.
        • Aleksic B.
        • Nakatochi M.
        • Shimamura T.
        • Okada T.
        • Uno Y.
        • et al.
        Comparative analyses of copy-number variation in autism spectrum disorder and schizophrenia reveal etiological overlap and biological insights.
        Cell Rep. 2018; 24: 2838-2856
        • Ramocki M.B.
        • Zoghbi H.Y.
        Failure of neuronal homeostasis results in common neuropsychiatric phenotypes.
        Nature. 2008; 455: 912-918
        • Cox D.M.
        • Butler M.G.
        The 15q11.2 BP1–BP2 microdeletion syndrome: A review.
        Int J Mol Sci. 2015; 16: 4068-4082
        • Grozeva D.
        • Conrad D.F.
        • Barnes C.P.
        • Hurles M.
        • Owen M.J.
        • O’Donovan M.C.
        • et al.
        Independent estimation of the frequency of rare CNVs in the UK population confirms their role in schizophrenia.
        Schizophr Res. 2012; 135: 1-7
        • Grayton H.M.
        • Fernandes C.
        • Rujescu D.
        • Collier D.A.
        Copy number variations in neurodevelopmental disorders.
        Prog Neurobiol. 2012; 99: 81-91
        • Vanlerberghe C.
        • Petit F.
        • Malan V.
        • Vincent-Delorme C.
        • Bouquillon S.
        • Boute O.
        • et al.
        15q11.2 microdeletion (BP1-BP2) and developmental delay, behaviour issues, epilepsy and congenital heart disease: A series of 52 patients.
        Eur J Med Genet. 2015; 58: 140-147
        • Nishimura Y.
        • Martin C.L.
        • Vazquez-Lopez A.
        • Spence S.J.
        • Alvarez-Retuerto A.I.
        • Sigman M.
        • et al.
        Genome-wide expression profiling of lymphoblastoid cell lines distinguishes different forms of autism and reveals shared pathways.
        Hum Mol Genet. 2007; 16: 1682-1698
        • van der Zwaag B.
        • Staal W.G.
        • Hochstenbach R.
        • Poot M.
        • Spierenburg H.A.
        • de Jonge M.V.
        • et al.
        A co-segregating microduplication of chromosome 15q11.2 pinpoints two risk genes for autism spectrum disorder.
        Am J Med Genet B Neuropsychiatr Genet. 2010; 153B: 960-966
        • Stefansson H.
        • Rujescu D.
        • Cichon S.
        • Pietiläinen O.P.H.
        • Ingason A.
        • Steinberg S.
        • et al.
        Large recurrent microdeletions associated with schizophrenia.
        Nature. 2008; 455: 232-236
        • Stefansson H.
        • Meyer-Lindenberg A.
        • Steinberg S.
        • Magnusdottir B.
        • Morgen K.
        • Arnarsdottir S.
        • et al.
        CNVs conferring risk of autism or schizophrenia affect cognition in controls.
        Nature. 2014; 505: 361-366
        • Woo Y.J.
        • Kanellopoulos A.K.
        • Hemati P.
        • Kirschen J.
        • Nebel R.A.
        • Wang T.
        • et al.
        Domain-specific cognitive impairments in humans and flies with reduced CYFIP1 dosage.
        Biol Psychiatry. 2019; 86: 306-314
        • Silva A.I.
        • Kirov G.
        • Kendall K.M.
        • Bracher-Smith M.
        • Wilkinson L.S.
        • Hall J.
        • et al.
        Analysis of diffusion tensor imaging data from the UK Biobank confirms dosage effect of 15q11.2 copy number variation on white matter and shows association with cognition [published online ahead of print Mar 3].
        Biol Psychiatry. 2021;
        • Silva A.I.
        • Ulfarsson M.O.
        • Stefansson H.
        • Gustafsson O.
        • Walters G.B.
        • Linden D.E.J.
        • et al.
        Reciprocal white matter changes associated with copy number variation at 15q11.2 BP1-BP2: A diffusion tensor imaging study.
        Biol Psychiatry. 2019; 85: 563-572
        • van der Meer D.
        • Sønderby I.E.
        • Kaufmann T.
        • Walters G.B.
        • Abdellaoui A.
        • et al.
        • Writing Committee for the ENIGMA-CNV Working Group
        Association of copy number variation of the 15q11.2 BP1-BP2 region with cortical and subcortical morphology and cognition.
        JAMA Psychiatry. 2020; 77: 420-430
        • Napoli I.
        • Mercaldo V.
        • Boyl P.P.
        • Eleuteri B.
        • Zalfa F.
        • De Rubeis S.
        • et al.
        The fragile X syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP.
        Cell. 2008; 134: 1042-1054
        • De Rubeis S.
        • Pasciuto E.
        • Li K.W.
        • Fernández E.
        • Di Marino D.
        • Buzzi A.
        • et al.
        CYFIP1 coordinates mRNA translation and cytoskeleton remodeling to ensure proper dendritic spine formation.
        Neuron. 2013; 79: 1169-1182
        • Pathania M.
        • Davenport E.C.
        • Muir J.
        • Sheehan D.F.
        • López-Doménech G.
        • Kittler J.T.
        The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines.
        Transl Psychiatry. 2014; 4: e374
        • Oguro-Ando A.
        • Rosensweig C.
        • Herman E.
        • Nishimura Y.
        • Werling D.
        • Bill B.R.
        • et al.
        Increased CYFIP1 dosage alters cellular and dendritic morphology and dysregulates mTOR.
        Mol Psychiatry. 2015; 20: 1069-1078
        • Bachmann S.O.
        • Sledziowska M.
        • Cross E.
        • Kalbassi S.
        • Waldron S.
        • Chen F.
        • et al.
        Behavioral training rescues motor deficits in Cyfip1 haploinsufficiency mouse model of autism spectrum disorders.
        Transl Psychiatry. 2019; 9: 29
        • Bozdagi O.
        • Sakurai T.
        • Dorr N.
        • Pilorge M.
        • Takahashi N.
        • Buxbaum J.D.
        Haploinsufficiency of Cyfip1 produces fragile X-like phenotypes in mice.
        PLoS One. 2012; 7e42422
        • Davenport E.C.
        • Szulc B.R.
        • Drew J.
        • Taylor J.
        • Morgan T.
        • Higgs N.F.
        • et al.
        Autism and schizophrenia-associated CYFIP1 regulates the balance of synaptic excitation and inhibition.
        Cell Rep. 2019; 26: 2037-2051.e6
        • Domínguez-Iturza N.
        • Lo A.C.
        • Shah D.
        • Armendáriz M.
        • Vannelli A.
        • Mercaldo V.
        • et al.
        The autism- and schizophrenia-associated protein CYFIP1 regulates bilateral brain connectivity and behaviour.
        Nat Commun. 2019; 10: 3454
        • Silva A.I.
        • Haddon J.E.
        • Ahmed Syed Y.
        • Trent S.
        • Lin T.E.
        • Patel Y.
        • et al.
        Cyfip1 haploinsufficient rats show white matter changes, myelin thinning, abnormal oligodendrocytes and behavioural inflexibility.
        Nat Commun. 2019; 10: 3455
        • Fricano-Kugler C.
        • Gordon A.
        • Shin G.
        • Gao K.
        • Nguyen J.
        • Berg J.
        • et al.
        CYFIP1 overexpression increases fear response in mice but does not affect social or repetitive behavioral phenotypes.
        Mol Autism. 2019; 10: 25
        • Babbs R.K.
        • Beierle J.A.
        • Ruan Q.T.
        • Kelliher J.C.
        • Chen M.M.
        • Feng A.X.
        • et al.
        Cyfip1 haploinsufficiency increases compulsive-like behavior and modulates palatable food intake in mice: Dependence on Cyfip2 genetic background, parent-of origin, and Sex.
        G3 (Bethesda). 2019; 9: 3009-3022
        • Chung L.
        • Wang X.
        • Zhu L.
        • Towers A.J.
        • Cao X.
        • Kim I.H.
        • Jiang Y.H.
        Parental origin impairment of synaptic functions and behaviors in cytoplasmic FMRP interacting protein 1 (Cyfip1) deficient mice.
        Brain Res. 2015; 1629: 340-350
        • Zhao Q.
        • Li T.
        • Zhao X.
        • Huang K.
        • Wang T.
        • Li Z.
        • et al.
        Rare CNVs and tag SNPs at 15q11.2 are associated with schizophrenia in the Han Chinese population.
        Schizophr Bull. 2013; 39: 712-719
        • Waltes R.
        • Duketis E.
        • Knapp M.
        • Anney R.J.L.
        • Huguet G.
        • Schlitt S.
        • et al.
        Common variants in genes of the postsynaptic FMRP signalling pathway are risk factors for autism spectrum disorders.
        Hum Genet. 2014; 133: 781-792
        • Noroozi R.
        • Omrani M.D.
        • Sayad A.
        • Taheri M.
        • Ghafouri-Fard S.
        Cytoplasmic FMRP interacting protein 1/2 (CYFIP1/2) expression analysis in autism.
        Metab Brain Dis. 2018; 33: 1353-1358
        • Wang J.
        • Tao Y.
        • Song F.
        • Sun Y.
        • Ott J.
        • Saffen D.
        Common regulatory variants of CYFIP1 contribute to susceptibility for autism spectrum disorder (ASD) and classical autism.
        Ann Hum Genet. 2015; 79: 329-340
        • Silverman J.L.
        • Yang M.
        • Lord C.
        • Crawley J.N.
        Behavioural phenotyping assays for mouse models of autism.
        Nat Rev Neurosci. 2010; 11: 490-502
        • van den Buuse M.
        Modeling the positive symptoms of schizophrenia in genetically modified mice: Pharmacology and methodology aspects.
        Schizophr Bull. 2010; 36: 246-270
        • Rapin I.
        • Tuchman R.F.
        Autism: Definition, neurobiology, screening, diagnosis.
        Pediatr Clin North Am. 2008; 55 (viii): 1129-1146
        • Deacon R.M.J.
        Digging and marble burying in mice: Simple methods for in vivo identification of biological impacts.
        Nat Protoc. 2006; 1: 122-124
        • Sadakata T.
        • Washida M.
        • Iwayama Y.
        • Shoji S.
        • Sato Y.
        • Ohkura T.
        • et al.
        Autistic-like phenotypes in Cadps2-knockout mice and aberrant CADPS2 splicing in autistic patients.
        J Clin Invest. 2007; 117: 931-943
        • Satoh Y.
        • Endo S.
        • Nakata T.
        • Kobayashi Y.
        • Yamada K.
        • Ikeda T.
        • et al.
        ERK2 contributes to the control of social behaviors in mice.
        J Neurosci. 2011; 31: 11953-11967
        • Won H.
        • Lee H.R.
        • Gee H.Y.
        • Mah W.
        • Kim J.I.
        • Lee J.
        • et al.
        Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function.
        Nature. 2012; 486: 261-265
        • Zhao J.
        • Ohsumi T.K.
        • Kung J.T.
        • Ogawa Y.
        • Grau D.J.
        • Sarma K.
        • et al.
        Genome-wide identification of polycomb-associated RNAs by RIP-seq.
        Mol Cell. 2010; 40: 939-953
        • Darnell J.C.
        • Van Driesche S.J.
        • Zhang C.
        • Hung K.Y.
        • Mele A.
        • Fraser C.E.
        • et al.
        FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism.
        Cell. 2011; 146: 247-261
        • Panja D.
        • Kenney J.W.
        • D’Andrea L.
        • Zalfa F.
        • Vedeler A.
        • Wibrand K.
        • et al.
        Two-stage translational control of dentate gyrus LTP consolidation is mediated by sustained BDNF-TrkB signaling to MNK.
        Cell Rep. 2014; 9: 1430-1445
        • Aviner R.
        • Geiger T.
        • Elroy-Stein O.
        Genome-wide identification and quantification of protein synthesis in cultured cells and whole tissues by puromycin-associated nascent chain proteomics (PUNCH-P).
        Nat Protoc. 2014; 9: 751-760
        • Feng W.
        • Zhang M.
        Organization and dynamics of PDZ-domain-related supramodules in the postsynaptic density.
        Nat Rev Neurosci. 2009; 10: 87-99
        • Yoon K.J.
        • Nguyen H.N.
        • Ursini G.
        • Zhang F.
        • Kim N.S.
        • Wen Z.
        • et al.
        Modeling a genetic risk for schizophrenia in iPSCs and mice reveals neural stem cell deficits associated with adherens junctions and polarity.
        Cell Stem Cell. 2014; 15: 79-91
        • Fromer M.
        • Pocklington A.J.
        • Kavanagh D.H.
        • Williams H.J.
        • Dwyer S.
        • Gormley P.
        • et al.
        De novo mutations in schizophrenia implicate synaptic networks.
        Nature. 2014; 506: 179-184
        • Lakhan S.E.
        • Caro M.
        • Hadzimichalis N.
        NMDA receptor activity in neuropsychiatric disorders.
        Front Psychiatry. 2013; 4: 52
        • Lee E.J.
        • Choi S.Y.
        • Kim E.
        NMDA receptor dysfunction in autism spectrum disorders.
        Curr Opin Pharmacol. 2015; 20: 8-13
        • van den Buuse M.
        • Halley P.
        • Hill R.
        • Labots M.
        • Martin S.
        Altered N-methyl-D-aspartate receptor function in reelin heterozygous mice: Male-female differences and comparison with dopaminergic activity.
        Prog Neuropsychopharmacol Biol Psychiatry. 2012; 37: 237-246
        • Zhou X.
        • Zheng F.
        • Moon C.
        • Schlüter O.M.
        • Wang H.
        Bi-directional regulation of CaMKIIalpha phosphorylation at Thr286 by NMDA receptors in cultured cortical neurons.
        J Neurochem. 2012; 122: 295-307
        • Waxman E.A.
        • Lynch D.R.
        N-methyl-D-aspartate receptor subtype mediated bidirectional control of p38 mitogen-activated protein kinase.
        J Biol Chem. 2005; 280: 29322-29333
        • Chung W.
        • Choi S.Y.
        • Lee E.
        • Park H.
        • Kang J.
        • Park H.
        • et al.
        Social deficits in IRSp53 mutant mice improved by NMDAR and mGluR5 suppression.
        Nat Neurosci. 2015; 18: 435-443
        • Stazi M.
        • Wirths O.
        Chronic memantine treatment ameliorates behavioral deficits, neuron loss, and impaired neurogenesis in a model of Alzheimer’s disease.
        Mol Neurobiol. 2021; 58: 204-216
        • Lockrow J.
        • Boger H.
        • Bimonte-Nelson H.
        • Granholm A.C.
        Effects of long-term memantine on memory and neuropathology in Ts65Dn mice, a model for Down syndrome.
        Behav Brain Res. 2011; 221: 610-622
        • Gao Y.
        • Payne R.S.
        • Schurr A.
        • Hougland T.
        • Lord J.
        • Herman L.
        • et al.
        Memantine reduces mania-like symptoms in animal models.
        Psychiatry Res. 2011; 188: 366-371
        • Blundell J.
        • Blaiss C.A.
        • Etherton M.R.
        • Espinosa F.
        • Tabuchi K.
        • Walz C.
        • et al.
        Neuroligin-1 deletion results in impaired spatial memory and increased repetitive behavior.
        J Neurosci. 2010; 30: 2115-2129
        • Zhou J.
        • Blundell J.
        • Ogawa S.
        • Kwon C.H.
        • Zhang W.
        • Sinton C.
        • et al.
        Pharmacological inhibition of mTORC1 suppresses anatomical, cellular, and behavioral abnormalities in neural-specific Pten knock-out mice.
        J Neurosci. 2009; 29: 1773-1783
        • Young D.M.
        • Schenk A.K.
        • Yang S.B.
        • Jan Y.N.
        • Jan L.Y.
        Altered ultrasonic vocalizations in a tuberous sclerosis mouse model of autism.
        Proc Natl Acad Sci U S A. 2010; 107: 11074-11079
        • Tsai P.T.
        • Hull C.
        • Chu Y.
        • Greene-Colozzi E.
        • Sadowski A.R.
        • Leech J.M.
        • et al.
        Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice.
        Nature. 2012; 488: 647-651
        • Santini E.
        • Huynh T.N.
        • MacAskill A.F.
        • Carter A.G.
        • Pierre P.
        • Ruggero D.
        • et al.
        Exaggerated translation causes synaptic and behavioural aberrations associated with autism.
        Nature. 2013; 493: 411-415
        • Gkogkas C.G.
        • Khoutorsky A.
        • Ran I.
        • Rampakakis E.
        • Nevarko T.
        • Weatherill D.B.
        • et al.
        Autism-related deficits via dysregulated eIF4E-dependent translational control.
        Nature. 2013; 493: 371-377
        • Topol A.
        • English J.A.
        • Flaherty E.
        • Rajarajan P.
        • Hartley B.J.
        • Gupta S.
        • et al.
        Increased abundance of translation machinery in stem cell-derived neural progenitor cells from four schizophrenia patients.
        Transl Psychiatry. 2015; 5e662
        • English J.A.
        • Fan Y.
        • Föcking M.
        • Lopez L.M.
        • Hryniewiecka M.
        • Wynne K.
        • et al.
        Reduced protein synthesis in schizophrenia patient-derived olfactory cells.
        Transl Psychiatry. 2015; 5: e663
        • Schizophrenia Working Group of the Psychiatric Genomics Consortium
        Biological insights from 108 schizophrenia-associated genetic loci.
        Nature. 2014; 511: 421-427
        • O’Roak B.J.
        • Deriziotis P.
        • Lee C.
        • Vives L.
        • Schwartz J.J.
        • Girirajan S.
        • et al.
        Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations.
        Nat Genet. 2011; 43: 585-589
        • De Rubeis S.
        • He X.
        • Goldberg A.P.
        • Poultney C.S.
        • Samocha K.
        • Cicek A.E.
        • et al.
        Synaptic, transcriptional and chromatin genes disrupted in autism.
        Nature. 2014; 515: 209-215
        • Takasaki Y.
        • Koide T.
        • Wang C.
        • Kimura H.
        • Xing J.
        • Kushima I.
        • et al.
        Mutation screening of GRIN2B in schizophrenia and autism spectrum disorder in a Japanese population.
        Sci Rep. 2016; 6: 33311
        • Li W.
        • Ghose S.
        • Gleason K.
        • Begovic A.
        • Perez J.
        • Bartko J.
        • et al.
        Synaptic proteins in the hippocampus indicative of increased neuronal activity in CA3 in schizophrenia.
        Am J Psychiatry. 2015; 172: 373-382
        • Akbarian S.
        • Sucher N.J.
        • Bradley D.
        • Tafazzoli A.
        • Trinh D.
        • Hetrick W.P.
        • et al.
        Selective alterations in gene expression for NMDA receptor subunits in prefrontal cortex of schizophrenics.
        J Neurosci. 1996; 16: 19-30
        • Mohn A.R.
        • Gainetdinov R.R.
        • Caron M.G.
        • Koller B.H.
        Mice with reduced NMDA receptor expression display behaviors related to schizophrenia.
        Cell. 1999; 98: 427-436
        • Belforte J.E.
        • Zsiros V.
        • Sklar E.R.
        • Jiang Z.
        • Yu G.
        • Li Y.
        • et al.
        Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes.
        Nat Neurosci. 2010; 13: 76-83
        • Gandal M.J.
        • Anderson R.L.
        • Billingslea E.N.
        • Carlson G.C.
        • Roberts T.P.L.
        • Siegel S.J.
        Mice with reduced NMDA receptor expression: More consistent with autism than schizophrenia?.
        Genes Brain Behav. 2012; 11: 740-750
        • Santini E.
        • Huynh T.N.
        • Longo F.
        • Koo S.Y.
        • Mojica E.
        • D’Andrea L.
        • et al.
        Reducing eIF4E-eIF4G interactions restores the balance between protein synthesis and actin dynamics in fragile X syndrome model mice.
        Sci Signal. 2017; 10eaan0665