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Glutamatergic candidate genes in autism spectrum disorder: an overview

  • Psychiatry and Preclinical Psychiatric Studies - Review article
  • Published:
Journal of Neural Transmission Aims and scope Submit manuscript

Abstract

Autism spectrum disorders (ASD) are neurodevelopmental disorders with early onset in childhood. Most of the risk for ASD can be explained by genetic variants that act in interaction with biological environmental risk factors. However, the architecture of the genetic components is still unclear. Genetic studies and subsequent systems biological approaches described converging functional effects of identified genes towards pathways relevant for neuronal signalling. Mouse models suggest an aberrant synaptic plasticity at the neuropathological level, which is believed to be conferred by dysregulation of long-term potentiation or depression of neuronal connections. A central pathway regulating these mechanisms is glutamatergic signalling. Here, we hypothesized that susceptibility genes for ASD are enriched for components of this pathway. To further understand the impact of ASD risk genes on the glutamatergic pathway, we performed a systematic review using the literature database “pubmed” and the “AutismKB” knowledgebase. We provide an overview of the glutamatergic system in typical brain function and development, and summarize findings from linkage, association, copy number variants, and sequencing studies in ASD to provide a comprehensive picture of the glutamatergic landscape of ASD genetics. Genetic variants associated with ASD were enriched in glutamatergic pathways, affecting receptor signalling, metabolism and transport. Furthermore, in genetically modified mouse models for ASD, pharmacological compounds acting on ionotropic or metabotropic receptor activity are able to rescue ASD reminscent phenotypes. We conclude that glutamatergic genetic risk factors for ASD show a complex pattern and further studies are needed to fully understand its mechanisms, before translation of findings into clinical applications and individualized treatment approaches will be possible.

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References

  • Allen-Brady K, Miller J, Matsunami N, Stevens J, Block H, Farley M, Krasny L, Pingree C, Lainhart J, Leppert M, McMahon WM, Coon H (2009) A high-density SNP genome-wide linkage scan in a large autism extended pedigree. Mol Psychiatry 14(6):590–600

    CAS  PubMed  Google Scholar 

  • Allen-Brady K, Robison R, Cannon D, Varvil T, Villalobos M, Pingree C, Leppert MF, Miller J, McMahon WM, Coon H (2010) Genome-wide linkage in Utah autism pedigrees. Mol Psychiatry 15(10):1006–1015

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ambrosini A, Bresciani L, Fracchia S, Brunello N, Racagni G (1995) Metabotropic glutamate receptors negatively coupled to adenylate cyclase inhibit N-methyl-d-aspartate receptor activity and prevent neurotoxicity in mesencephalic neurons in vitro. Mol Pharmacol 47(5):1057–1064

    CAS  PubMed  Google Scholar 

  • American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders (DSM-5™), 5th edn

  • Anderson CM, Swanson RA (2000) Astrocyte glutamate transport: review of properties, regulation, and physiological functions. Glia 32(1):1–14

    CAS  PubMed  Google Scholar 

  • Anney R, Klei L, Pinto D, Almeida J, Bacchelli E, Baird G, Bolshakova N, Bolte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Casey J, Conroy J, Correia C, Corsello C, Crawford EL, Jonge M, Delorme R, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Fombonne E, Gilbert J, Gillberg C, Glessner JT, Green A, Green J, Guter SJ, Heron EA, Holt R, Howe JL, Hughes G, Hus V, Igliozzi R, Jacob S, Kenny GP, Kim C, Kolevzon A, Kustanovich V, Lajonchere CM, Lamb JA, Law-Smith M, Leboyer M, Le Couteur A, Leventhal BL, Liu X, Lombard F, Lord C, Lotspeich L, Lund SC, Magalhaes TR, Mantoulan C, McDougle CJ, Melhem NM, Merikangas A, Minshew NJ, Mirza GK, Munson J, Noakes C, Nygren G, Papanikolaou K, Pagnamenta AT, Parrini B, Paton T, Pickles A, Posey DJ, Poustka F, Ragoussis J, Regan R, Roberts W, Roeder K, Roge B, Rutter ML, Schlitt S, Shah N, Sheffield VC, Soorya L, Sousa I, Stoppioni V, Sykes N, Tancredi R, Thompson AP, Thomson S, Tryfon A, Tsiantis J, van Engeland H, Vincent JB, Volkmar F, Vorstman J, Wallace S, Wing K, Wittemeyer K, Wood S, Zurawiecki D, Zwaigenbaum L, Bailey AJ, Battaglia A, Cantor RM, Coon H, Cuccaro ML, Dawson G, Ennis S, Freitag CM, Geschwind DH, Haines JL, Klauck SM, McMahon WM, Maestrini E, Miller J, Monaco AP, Nelson SF, Nurnberger JI, Oliveira G, Parr JR, Pericak-Vance MA, Piven J, Schellenberg GD, Scherer SW, Vicente AM, Wassink TH, Wijsman EM, Betancur C, Buxbaum JD, Cook EH, Gallagher L, Gill M, Hallmayer J, Paterson AD, Sutcliffe JS, Szatmari P, Vieland VJ, Hakonarson H, Devlin B, Anney R, Klei L, Pinto D, Almeida J, Bacchelli E, Baird G, Bolshakova N, Bölte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Casey J, Conroy J, Correia C, Corsello C, Crawford EL, Jonge M, Delorme R, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Fombonne E, Gilbert J, Gillberg C, Glessner JT, Green A, Green J, Guter SJ, Heron EA, Holt R, Howe JL, Hughes G, Hus V, Igliozzi R, Jacob S, Kenny GP, Kim C, Kolevzon A, Kustanovich V, Lajonchere CM, Lamb JA, Law-Smith M, Leboyer M, Le Couteur A, Leventhal BL, Liu X, Lombard F, Lord C, Lotspeich L, Lund SC, Magalhaes TR, Mantoulan C, McDougle CJ, Melhem NM, Merikangas A, Minshew NJ, Mirza GK, Munson J, Noakes C, Nygren G, Papanikolaou K, Pagnamenta AT, Parrini B, Paton T, Pickles A, Posey DJ, Poustka F, Ragoussis J, Regan R, Roberts W, Roeder K, Roge B, Rutter ML, Schlitt S, Shah N, Sheffield VC, Soorya L, Sousa I, Stoppioni V, Sykes N, Tancredi R, Thompson AP, Thomson S, Tryfon A, Tsiantis J, van Engeland H, Vincent JB, Volkmar F, Vorstman J, Wallace S, Wing K, Wittemeyer K, Wood S, Zurawiecki D, Zwaigenbaum L, Bailey AJ, Battaglia A, Cantor RM, Coon H, Cuccaro ML, Dawson G, Ennis S, Freitag CM, Geschwind DH, Haines JL, Klauck SM, McMahon WM, Maestrini E, Miller J, Monaco AP, Nelson SF, Nurnberger JI, Oliveira G, Parr JR, Pericak-Vance MA, Piven J, Schellenberg GD, Scherer SW, Vicente AM, Wassink TH, Wijsman EM, Betancur C, Buxbaum JD, Cook EH, Gallagher L, Gill M, Hallmayer J, Paterson AD, Sutcliffe JS, Szatmari P, Vieland VJ, Hakonarson H, Devlin B (2012) Individual common variants exert weak effects on the risk for autism spectrum disorderspi. Hum Mol Genet 21:4781–4792

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ascano M, Mukherjee N, Bandaru P, Miller JB, Nusbaum JD, Corcoran DL, Langlois C, Munschauer M, Dewell S, Hafner M, Williams Z, Ohler U, Tuschl T (2012) FMRP targets distinct mRNA sequence elements to regulate protein expression. Nature 492(7429):382–386

    CAS  PubMed Central  PubMed  Google Scholar 

  • Auranen M, Vanhala R, Varilo T, Ayers K, Kempas E, Ylisaukko-Oja T, Sinsheimer JS, Peltonen L, Jarvela I (2002) A genomewide screen for autism-spectrum disorders. Evidence for a major susceptibility locus on chromosome 3q25–27. Am J Hum Genet 71(4):777–790

    PubMed Central  PubMed  Google Scholar 

  • Baird G, Simonoff E, Pickles A, Chandler S, Loucas T, Meldrum D, Charman T (2006) Prevalence of disorders of the autism spectrum in a population cohort of children in South Thames: the Special Needs and Autism Project (SNAP). Lancet 368(9531):210–215

    PubMed  Google Scholar 

  • Bakkaloglu B, O’Roak BJ, Louvi A, Gupta AR, Abelson JF, Morgan TM, Chawarska K, Klin A, Ercan-Sencicek AG, Stillman AA, Tanriover G, Abrahams BS, Duvall JA, Robbins EM, Geschwind DH, Biederer T, Gunel M, Lifton RP, State MW (2008) Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders. Am J Hum Genet 82(1):165–173

    CAS  PubMed Central  PubMed  Google Scholar 

  • Balciuniene J, Feng N, Iyadurai K, Hirsch B, Charnas L, Bill BR, Easterday MC, Staaf J, Oseth L, Czapansky-Beilman D, Avramopoulos D, Thomas GH, Borg A, Valle D, Schimmenti LA, Selleck SB (2007) Recurrent 10q22–q23 deletions: a genomic disorder on 10q associated with cognitive and behavioral abnormalities. Am J Hum Genet 80(5):938–947

    CAS  PubMed Central  PubMed  Google Scholar 

  • Barbado M, Fablet K, Ronjat M, de Waard M (2009) Gene regulation by voltage-dependent calcium channels. Biochim Biophys Acta 1793(6):1096–1104

    CAS  PubMed  Google Scholar 

  • Barnby G, Abbott A, Sykes N, Morris A, Weeks DE, Mott R, Lamb J, Bailey AJ, Monaco AP (2005) Candidate-gene screening and association analysis at the autism-susceptibility locus on chromosome 16p: evidence of Association at GRIN2A and ABATevidence of association at GRIN2A and ABAT. Am J Hum Genet 76(6):950–966

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bartsch O, Labonté J, Albrecht B, Wieczorek D, Lechno S, Zechner U, Haaf T (2010) Two patients with EP300 mutations and facial dysmorphism different from the classic Rubinstein–Taybi syndrome. Am J Med Genet A 152A(1):181–184

    PubMed  Google Scholar 

  • Bassell GJ, Warren ST (2008) Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function. Neuron 60(2):201–214

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bassuk AG, Geraghty E, Wu S, Mullen SA, Berkovic SF, Scheffer IE, Mefford HC (2013) Deletions of 16p11.2 and 19p13.2 in a family with intellectual disability and generalized epilepsy. Am J Med Genet A 161A(7):1722–1725

    PubMed  Google Scholar 

  • Bateup HS, Johnson CA, Denefrio CL, Saulnier JL, Kornacker K, Sabatini BL (2013) Excitatory/inhibitory synaptic imbalance leads to hippocampal hyperexcitability in mouse models of tuberous sclerosis. Neuron 78(3):510–522

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bauer JW, Brandl C, Haubenreisser O, Wimmer B, Weber M, Karl T, Klausegger A, Breitenbach M, Hintner H, von der Haar Tobias, Tuite MF, Breitenbach-Koller L (2013) Specialized yeast ribosomes: a customized tool for selective mRNA translation. PLoS One 8(7):e67609

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bear MF, Huber KM, Warren ST (2004) The mGluR theory of fragile X mental retardation. Trends Neurosci 27(7):370–377

    CAS  PubMed  Google Scholar 

  • Berkel S, Marshall CR, Weiss B, Howe J, Roeth R, Moog U, Endris V, Roberts W, Szatmari P, Pinto D, Bonin M, Riess A, Engels H, Sprengel R, Scherer SW, Rappold GA (2010) Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation. Nat Genet 42(6):489–491

    CAS  PubMed  Google Scholar 

  • Betancur C (2011) Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting. Brain Res 1380:42–77

    CAS  PubMed  Google Scholar 

  • Bonati MT, Finelli P, Giardino D, Gottardi G, Roberts W, Larizza L (2005) Trisomy 15q25.2-qter in an autistic child: genotype-phenotype correlations. Am J Med Genet A 133A(2):184–188

    PubMed  Google Scholar 

  • Bozdagi O, Sakurai T, Papapetrou D, Wang X, Dickstein DL, Takahashi N, Kajiwara Y, Yang M, Katz AM, Scattoni ML, Harris MJ, Saxena R, Silverman JL, Crawley JN, Zhou Q, Hof PR, Buxbaum JD (2010) Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication. Mol Autism 1(1):15

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bremer A, Giacobini M, Eriksson M, Gustavsson P, Nordin V, Fernell E, Gillberg C, Nordgren A, Uppströmer A, Anderlid B, Nordenskjöld M, Schoumans J (2011) Copy number variation characteristics in subpopulations of patients with autism spectrum disorders. Am J Med Genet B Neuropsychiatr Genet 156(2):115–124

    PubMed  Google Scholar 

  • Bristot Silvestrin R, Bambini-Junior V, Galland F, Daniele Bobermim L, Quincozes-Santos A, Torres Abib R, Zanotto C, Batassini C, Brolese G, Gonçalves C, Riesgo R, Gottfried C (2013) Animal model of autism induced by prenatal exposure to valproate: altered glutamate metabolism in the hippocampus. Brain Res 1495:52–60

    CAS  PubMed  Google Scholar 

  • Brostrom CO, Brostrom MA (1990) Calcium-dependent regulation of protein synthesis in intact mammalian cells. Annu Rev Physiol 52:577–590

    CAS  PubMed  Google Scholar 

  • Bucan M, Abrahams BS, Wang K, Glessner JT, Herman EI, Sonnenblick LI, Alvarez Retuerto AI, Imielinski M, Hadley D, Bradfield JP, Kim C, Gidaya NB, Lindquist I, Hutman T, Sigman M, Kustanovich V, Lajonchere CM, Singleton A, Kim J, Wassink TH, McMahon WM, Owley T, Sweeney JA, Coon H, Nurnberger JI, Li M, Cantor RM, Minshew NJ, Sutcliffe JS, Cook EH, Dawson G, Buxbaum JD, Grant SF, Schellenberg GD, Geschwind DH, Hakonarson H (2009) Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes. PLoS Genet 5(6):e1000536

    PubMed Central  PubMed  Google Scholar 

  • Buxbaum JD, Silverman JM, Smith CJ, Kilifarski M, Reichert J, Hollander E, Lawlor BA, Fitzgerald M, Greenberg DA, Davis KL (2001) Evidence for a susceptibility gene for autism on chromosome 2 and for genetic heterogeneity. Am J Hum Genet 68(6):1514–1520

    CAS  PubMed Central  PubMed  Google Scholar 

  • Buxbaum JD, Silverman J, Keddache M, Smith CJ, Hollander E, Ramoz N, Reichert JG (2004) Linkage analysis for autism in a subset families with obsessive-compulsive behaviors. Evidence for an autism susceptibility gene on chromosome 1 and further support for susceptibility genes on chromosome 6 and 19. Mol Psychiatry 9(2):144–150

    CAS  PubMed  Google Scholar 

  • Carlson GC (2012) Glutamate receptor dysfunction and drug targets across models of autism spectrum disorders. Pharmacol Biochem Behav 100(4):850–854

    CAS  PubMed Central  PubMed  Google Scholar 

  • Casey JP, Magalhaes T, Conroy JM, Regan R, Shah N, Anney R, Shields DC, Abrahams BS, Almeida J, Bacchelli E, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bolton PF, Bourgeron T, Brennan S, Cali P, Correia C, Corsello C, Coutanche M, Dawson G, de Jonge M, Delorme R, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Foley S, Fombonne E, Freitag CM, Gilbert J, Gillberg C, Glessner JT, Green J, Guter SJ, Hakonarson H, Holt R, Hughes G, Hus V, Igliozzi R, Kim C, Klauck SM, Kolevzon A, Lamb JA, Leboyer M, Le Couteur A, Leventhal BL, Lord C, Lund SC, Maestrini E, Mantoulan C, Marshall CR, McConachie H, McDougle CJ, McGrath J, McMahon WM, Merikangas A, Miller J, Minopoli F, Mirza GK, Munson J, Nelson SF, Nygren G, Oliveira G, Pagnamenta AT, Papanikolaou K, Parr JR, Parrini B, Pickles A, Pinto D, Piven J, Posey DJ, Poustka A, Poustka F, Ragoussis J, Roge B, Rutter ML, Sequeira AF, Soorya L, Sousa I, Sykes N, Stoppioni V, Tancredi R, Tauber M, Thompson AP, Thomson S, Tsiantis J, van Engeland H, Vincent JB, Volkmar F, Vorstman JAS, Wallace S, Wang K, Wassink TH, White K, Wing K, Wittemeyer K, Yaspan BL, Zwaigenbaum L, Betancur C, Buxbaum JD, Cantor RM, Cook EH, Coon H, Cuccaro ML, Geschwind DH, Haines JL, Hallmayer J, Monaco AP, Nurnberger JI, Pericak-Vance MA, Schellenberg GD, Scherer SW, Sutcliffe JS, Szatmari P, Vieland VJ, Wijsman EM, Green A, Gill M, Gallagher L, Vicente A, Ennis S (2012) A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder. Hum Genet 131(4):565–579

    PubMed Central  PubMed  Google Scholar 

  • Centers for Disease Control and Prevention (CDC) (2009) Prevalence of autism spectrum disorders—Autism and Developmental Disabilities Monitoring Network, United States, 2006. MMWR Surveill Summ 58(10):1–20

    Google Scholar 

  • Chahrour M, Jung SY, Shaw C, Zhou X, Wong Stephen T C, Qin J, Zoghbi HY (2008) MeCP2, a key contributor to neurological disease, activates and represses transcription. Science 320(5880):1224–1229

    CAS  PubMed Central  PubMed  Google Scholar 

  • Chao HT, Zoghbi HY, Rosenmund C (2007) MeCP2 controls excitatory synaptic strength by regulating glutamatergic synapse number. Neuron 56(1):58–65

    CAS  PubMed Central  PubMed  Google Scholar 

  • Chen C, Lin S, Chern S, Tsai F, Wu P, Lee C, Chen Y, Chen W, Wang W (2010) A de novo 7.9 Mb deletion in 22q13.2 → qter in a boy with autistic features, epilepsy, developmental delay, atopic dermatitis and abnormal immunological findings. Eur J Med Genet 53(5):329–332

    PubMed  Google Scholar 

  • Chen Y, Matsushita M, Girirajan S, Lisowski M, Sun E, Sul Y, Bernier R, Estes A, Dawson G, Minshew N, Shellenberg GD, Eichler EE, Rieder MJ, Nickerson DA, Tsuang DW, Tsuang MT, Wijsman EM, Raskind WH, Brkanac Z (2012) Evidence for involvement of GNB1L in autism. Am J Med Genet B Neuropsychiatr Genet 159B(1):61–71

    PubMed Central  PubMed  Google Scholar 

  • Chiyonobu T, Hayashi S, Kobayashi K, Morimoto M, Miyanomae Y, Nishimura A, Nishimoto A, Ito C, Imoto I, Sugimoto T, Jia Z, Inazawa J, Toda T (2007) Partial tandem duplication of GRIA3 in a male with mental retardation. Am J Med Genet A 143A(13):1448–1455

    CAS  PubMed  Google Scholar 

  • Chonchaiya W, Au J, Schneider A, Hessl D, Harris SW, Laird M, Mu Y, Tassone F, Nguyen DV, Hagerman RJ (2012) Increased prevalence of seizures in boys who were probands with the FMR1 premutation and co-morbid autism spectrum disorder. Hum Genet 131(4):581–589

    PubMed Central  PubMed  Google Scholar 

  • Choudhury PR, Lahiri S, Rajamma U (2012) Glutamate mediated signaling in the pathophysiology of autism spectrum disorders. Pharmacol Biochem Behav 100(4):841–849

    CAS  PubMed  Google Scholar 

  • Christian SL, Brune CW, Sudi J, Kumar RA, Liu S, KaraMohamed S, Badner JA, Matsui S, Conroy J, McQuaid D, Gergel J, Hatchwell E, Gilliam TC, Gershon ES, Nowak NJ, Dobyns WB, Cook EH (2008) Novel submicroscopic chromosomal abnormalities detected in autism spectrum disorder. Biol Psychol 63(12):1111–1117

    CAS  Google Scholar 

  • Chu Z, Hablitz JJ (2000) Quisqualate induces an inward current via mGluR activation in neocortical pyramidal neurons. Brain Res 879(1–2):88–92

    CAS  PubMed  Google Scholar 

  • Chung BHY, Drmic I, Marshall CR, Grafodatskaya D, Carter M, Fernandez BA, Weksberg R, Roberts W, Scherer SW (2011) Phenotypic spectrum associated with duplication of Xp11.22–p11.23 includes Autism Spectrum Disorder. Eur J Med Genet 54(5):e516–e520

    PubMed  Google Scholar 

  • Clifford S, Dissanayake C, Bui QM, Huggins R, Taylor AK, Loesch DZ (2007) Autism spectrum phenotype in males and females with fragile X full mutation and premutation. J Autism Dev Disord 37(4):738–747

    PubMed  Google Scholar 

  • Cuscó I, Medrano A, Gener B, Vilardell M, Gallastegui F, Villa O, González E, Rodríguez-Santiago B, Vilella E, Del Campo M, Pérez-Jurado LA (2009) Autism-specific copy number variants further implicate the phosphatidylinositol signaling pathway and the glutamatergic synapse in the etiology of the disorder. Hum Mol Genet 18(10):1795–1804

    PubMed Central  PubMed  Google Scholar 

  • Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65(1):1–105

    CAS  PubMed  Google Scholar 

  • Darnell JC, van Driesche SJ, Zhang C, Hung KYS, Mele A, Fraser CE, Stone EF, Chen C, Fak JJ, Chi SW, Licatalosi DD, Richter JD, Darnell RB (2011) FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146(2):247–261

    CAS  PubMed Central  PubMed  Google Scholar 

  • de Krom M, Staal WG, Ophoff RA, Hendriks J, Buitelaar J, Franke B, de Jonge Maretha V, Bolton P, Collier D, Curran S, van Engeland H, van Ree Jan M (2009) A common variant in DRD3 receptor is associated with autism spectrum disorder. Biol Psychiatry 65(7):625–630

    PubMed  Google Scholar 

  • de Ligt J, Willemsen MH, van Bon BWM, Kleefstra T, Yntema HG, Kroes T, Silfhout Vulto-van, Anneke T, Koolen DA, de Vries P, Gilissen C, del Rosario M, Hoischen A, Scheffer H, de Vries Bert B A, Brunner HG, Veltman JA, Vissers Lisenka E L M (2012) Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med 367(20):1921–1929

    PubMed  Google Scholar 

  • Devlin B, Scherer SW (2012) Genetic architecture in autism spectrum disorder. Curr Opin Genet Dev 22(3):229–237

    CAS  PubMed  Google Scholar 

  • Doherty J, Dingledine R (2002) The roles of metabotropic glutamate receptors in seizures and epilepsy. Curr Drug Targets CNS Neurol Disord 1(3):251–260

    CAS  PubMed  Google Scholar 

  • Dölen G, Osterweil E, Rao BS, Shankaranarayana Smith GB, Auerbach BD, Chattarji S, Bear MF (2007) Correction of fragile X syndrome in mice. Neuron 56(6):955–962

    PubMed Central  PubMed  Google Scholar 

  • Duffney LJ, Wei J, Cheng J, Liu W, Smith KR, Kittler JT, Yan Z (2013) Shank3 deficiency induces NMDA receptor hypofunction via an actin-dependent mechanism. J Neurosci 33(40):15767–15778

    CAS  PubMed Central  PubMed  Google Scholar 

  • Durand CM, Betancur C, Boeckers TM, Bockmann J, Chaste P, Fauchereau F, Nygren G, Rastam M, Gillberg IC, Anckarsater H, Sponheim E, Goubran-Botros H, Delorme R, Chabane N, Mouren-Simeoni MC, de Mas P, Bieth E, Roge B, Heron D, Burglen L, Gillberg C, Leboyer M, Bourgeron T (2007) Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet 39(1):25–27

    CAS  PubMed Central  PubMed  Google Scholar 

  • Durand CM, Perroy J, Loll F, Perrais D, Fagni L, Bourgeron T, Montcouquiol M, Sans N (2012) SHANK3 mutations identified in autism lead to modification of dendritic spine morphology via an actin-dependent mechanism. Mol Psychiatry 17(1):71–84

    CAS  PubMed Central  PubMed  Google Scholar 

  • Edens AC, Lyons MJ, Duron RM, Dupont BR, Holden KR (2011) Autism in two females with duplications involving Xp11.22–p11.23. Dev Med Child Neurol 53(5):463–466

    PubMed  Google Scholar 

  • Endele S, Rosenberger G, Geider K, Popp B, Tamer C, Stefanova I, Milh M, Kortüm F, Fritsch A, Pientka FK, Hellenbroich Y, Kalscheuer VM, Kohlhase J, Moog U, Rappold G, Rauch A, Ropers H, von Spiczak S, Tönnies H, Villeneuve N, Villard L, Zabel B, Zenker M, Laube B, Reis A, Wieczorek D, van Maldergem L, Kutsche K (2010) Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes. Nat Genet 42(11):1021–1026

    CAS  PubMed  Google Scholar 

  • Erickson CA, Posey DJ, Stigler KA, Mullett J, Katschke AR, McDougle CJ (2007) A retrospective study of memantine in children and adolescents with pervasive developmental disorders. Psychopharmacology 191(1):141–147

    CAS  PubMed  Google Scholar 

  • Fatemi SH (2008) The hyperglutamatergic hypothesis of autism. Prog Neuropsychopharmacol Biol Psychiatry 32(3):911 (author reply 912-3)

    CAS  PubMed  Google Scholar 

  • Feyder M, Karlsson R, Mathur P, Lyman M, Bock R, Momenan R, Munasinghe J, Scattoni ML, Ihne J, Camp M, Graybeal C, Strathdee D, Begg A, Alvarez VA, Kirsch P, Rietschel M, Cichon S, Walter H, Meyer-Lindenberg A, Grant Seth G N, Holmes A (2010) Association of mouse Dlg4 (PSD-95) gene deletion and human DLG4 gene variation with phenotypes relevant to autism spectrum disorders and Williams’ syndrome. Am J Psychiatry 167(12):1508–1517

    PubMed Central  PubMed  Google Scholar 

  • Finelli P, Natacci F, Bonati MT, Gottardi G, Engelen JJM, de Die-Smulders CEM, Sala M, Giardino D, Larizza L (2004) FISH characterisation of an identical (16)(p11.2p12.2) tandem duplication in two unrelated patients with autistic behaviour. J Med Genet 41(7):e90

    CAS  PubMed Central  PubMed  Google Scholar 

  • Fombonne E (2009) Epidemiology of pervasive developmental disorders. Pediatr Res 65(6):591–598

    PubMed  Google Scholar 

  • Freitag CM (2012) Autistische Störungen—state-of-the-art und neuere Entwicklungen (autistic disorders—the state of the art and recent findings: epidemiology, aetiology, diagnostic criteria, and therapeutic interventions). Z Kinder Jugendpsychiatr Psychother 40(3):139–148 (quiz 148-9)

    Google Scholar 

  • Gai X, Xie HM, Perin JC, Takahashi N, Murphy K, Wenocur AS, D’arcy M, O’Hara RJ, Goldmuntz E, Grice DE, Shaikh TH, Hakonarson H, Buxbaum JD, Elia J, White PS (2012) Rare structural variation of synapse and neurotransmission genes in autism. Mol Psychiatry 17(4):402–411

    CAS  PubMed Central  PubMed  Google Scholar 

  • Gauthier J, Spiegelman D, Piton A, Lafrenière RG, Laurent S, St-Onge J, Lapointe L, Hamdan FF, Cossette P, Mottron L, Fombonne E, Joober R, Marineau C, Drapeau P, Rouleau GA (2009) Novel de novo SHANK3 mutation in autistic patients. Am J Med Genet B Neuropsychiatr Genet 150B(3):421–424

    CAS  PubMed  Google Scholar 

  • Gilman SR, Iossifov I, Levy D, Ronemus M, Wigler M, Vitkup D (2011) Rare de novo variants associated with autism implicate a large functional network of genes involved in formation and function of synapses. Neuron 70(5):898–907

    CAS  PubMed Central  PubMed  Google Scholar 

  • Gkogkas CG, Khoutorsky A, Ran I, Rampakakis E, Nevarko T, Weatherill DB, Vasuta C, Yee S, Truitt M, Dallaire P, Major F, Lasko P, Ruggero D, Nader K, Lacaille J, Sonenberg N (2013) Autism-related deficits via dysregulated eIF4E-dependent translational control. Nature 493(7432):371–377

    CAS  PubMed Central  PubMed  Google Scholar 

  • Goizet C, Excoffier E, Taine L, Taupiac E, El Moneim AA, Arveiler B, Bouvard M, Lacombe D (2000) Case with autistic syndrome and chromosome 22q13.3 deletion detected by FISH. Am J Med Genet 96(6):839–844

    CAS  PubMed  Google Scholar 

  • Gregory SG, Connelly JJ, Towers AJ, Johnson J, Biscocho D, Markunas CA, Lintas C, Abramson RK, Wright HH, Ellis P, Langford CF, Worley G, Delong GR, Murphy SK, Cuccaro ML, Persico A, Pericak-Vance MA (2009) Genomic and epigenetic evidence for oxytocin receptor deficiency in autism. BMC Med 7:62

    PubMed Central  PubMed  Google Scholar 

  • Griswold AJ, Ma D, Cukier HN, Nations LD, Schmidt MA, Chung R, Jaworski JM, Salyakina D, Konidari I, Whitehead PL, Wright HH, Abramson RK, Williams SM, Menon R, Martin ER, Haines JL, Gilbert JR, Cuccaro ML, Pericak-Vance MA (2012) Evaluation of copy number variations reveals novel candidate genes in autism spectrum disorder-associated pathways. Hum Mol Genet 21(15):3513–3523

    Google Scholar 

  • Guilmatre A, Dubourg C, Mosca A, Legallic S, Goldenberg A, Drouin-Garraud V, Layet V, Rosier A, Briault S, Bonnet-Brilhault F, Laumonnier F, Odent S, Le Vacon G, Joly-Helas G, David V, Bendavid C, Pinoit J, Henry C, Impallomeni C, Germano E, Tortorella G, Di Rosa G, Barthelemy C, Andres C, Faivre L, Frébourg T, Saugier Veber P, Campion D (2009) Recurrent rearrangements in synaptic and neurodevelopmental genes and shared biologic pathways in schizophrenia, autism, and mental retardation. Arch Gen Psychiatry 66(9):947–956

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hall JG (1990) Genomic imprinting: review and relevance to human diseases. Am J Hum Genet 46(5):857–873

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hallmayer J, Cleveland S, Torres A, Phillips J, Cohen B, Torigoe T, Miller J, Fedele A, Collins J, Smith K, Lotspeich L, Croen LA, Ozonoff S, LaJonchere C, Grether JK, Risch N (2011) Genetic heritability and shared environmental factors among twin pairs with autism. Arch Gen Psychiatry 68(11):1095–1102

    PubMed  Google Scholar 

  • Hérault J, Perrot A, Barthélémy C, Büchler M, Cherpi C, Leboyer M, Sauvage D, Lelord G, Mallet J, Müh JP (1993) Possible association of c-Harvey-Ras-1 (HRAS-1) marker with autism. Psychiatry Res 46(3):261–267

    PubMed  Google Scholar 

  • Hérault J, Petit E, Martineau J, Perrot A, Lenoir P, Cherpi C, Barthélémy C, Sauvage D, Mallet J, Müh JP (1995) Autism and genetics: clinical approach and association study with two markers of HRAS gene. Am J Med Genet 60(4):276–281

    PubMed  Google Scholar 

  • Hosenbocus S, Chahal R (2013a) Amantadine: a review of use in child and adolescent psychiatry. J Can Acad Child Adolesc Psychiatry 22(1):55–60

    PubMed Central  PubMed  Google Scholar 

  • Hosenbocus S, Chahal R (2013b) Memantine: a review of possible uses in child and adolescent psychiatry. J Can Acad Child Adolesc Psychiatry 22(2):166–171

    PubMed Central  PubMed  Google Scholar 

  • Huguet G, Ey E, Bourgeron T (2013) The genetic landscapes of autism spectrum disorders. Annu Rev Genomics Hum Genet 14(1):130722103900008

    Google Scholar 

  • Hussman JP, Chung R, Griswold AJ, Jaworski JM, Salyakina D, Ma D, Konidari I, Whitehead PL, Vance JM, Martin ER, Cuccaro ML, Gilbert JR, Haines JL, Pericak-Vance MA (2011) A noise-reduction GWAS analysis implicates altered regulation of neurite outgrowth and guidance in autism. Mol Autism 2(1):1

    PubMed Central  PubMed  Google Scholar 

  • IMGSAC (1998) A full genome screen for autism with evidence for linkage to a region on chromosome 7q. International Molecular Genetic Study of Autism Consortium. Hum Mol Genet 7(3):571–578

    Google Scholar 

  • IMGSAC (2001a) A genomewide screen for autism: strong evidence for linkage to chromosomes 2q, 7q, and 16p. Am J Hum Genet 69(3):570–581

    Google Scholar 

  • IMGSAC (2001b) Further characterization of the autism susceptibility locus AUTS1 on chromosome 7q. Hum Mol Genet 10(9):973–982

    Google Scholar 

  • Iossifov I, Ronemus M, Levy D, Wang Z, Hakker I, Rosenbaum J, Yamrom B, Lee Y, Narzisi G, Leotta A, Kendall J, Grabowska E, Ma B, Marks S, Rodgers L, Stepansky A, Troge J, Andrews P, Bekritsky M, Pradhan K, Ghiban E, Kramer M, Parla J, Demeter R, Fulton LL, Fulton RS, Magrini VJ, Ye K, Darnell JC, Darnell RB, Mardis ER, Wilson RK, Schatz MC, McCombie WR, Wigler M (2012) De novo gene disruptions in children on the autistic spectrum. Neuron 74(2):285–299

    CAS  PubMed Central  PubMed  Google Scholar 

  • Jacquemont M, Sanlaville D, Redon R, Raoul O, Cormier-Daire V, Lyonnet S, Amiel J, Le Merrer M, Heron D, de Blois M, Prieur M, Vekemans M, Carter NP, Munnich A, Colleaux L, Philippe A (2006) Array-based comparative genomic hybridisation identifies high frequency of cryptic chromosomal rearrangements in patients with syndromic autism spectrum disorders. J Med Genet 43(11):843–849

    CAS  PubMed Central  PubMed  Google Scholar 

  • Jamain S, Betancur C, Quach H, Philippe A, Fellous M, Giros B, Gillberg C, Leboyer M, Bourgeron T (2002) Linkage and association of the glutamate receptor 6 gene with autism. Mol Psychiatry 7(3):302–310

    CAS  PubMed Central  PubMed  Google Scholar 

  • Javitt DC, Schoepp D, Kalivas PW, Volkow ND, Zarate C, Merchant K, Bear MF, Umbricht D, Hajos M, Potter WZ, Lee C (2011) Translating glutamate: from pathophysiology to treatment. Sci Transl Med 3(102):102mr2

    PubMed Central  PubMed  Google Scholar 

  • Jiang X, Yeung RS (2006) Regulation of microtubule-dependent protein transport by the TSC2/mammalian target of rapamycin pathway. Cancer Res 66(10):5258–5269

    CAS  PubMed  Google Scholar 

  • Jiang Y, Yuen RKC, Jin X, Wang M, Chen N, Wu X, Ju J, Mei J, Shi Y, He M, Wang G, Liang J, Wang Z, Cao D, Carter MT, Chrysler C, Drmic IE, Howe JL, Lau L, Marshall CR, Merico D, Nalpathamkalam T, Thiruvahindrapuram B, Thompson A, Uddin M, Walker S, Luo J, Anagnostou E, Zwaigenbaum L, Ring RH, Wang J, LaJonchere C, Wang J, Shih A, Szatmari P, Yang H, Dawson G, Li Y, Scherer SW (2013) Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing. Am J Hum Genet 93:249–263

    CAS  PubMed Central  PubMed  Google Scholar 

  • Johansson M, Gillberg C, Råstam M (2010) Autism spectrum conditions in individuals with Möbius sequence, CHARGE syndrome and oculo-auriculo-vertebral spectrum: diagnostic aspects. Res Dev Disabil 31(1):9–24

    PubMed  Google Scholar 

  • Kelleher RJ, Bear MF (2008) The autistic neuron: troubled translation? Cell 135(3):401–406

    CAS  PubMed  Google Scholar 

  • Kelleher RJ, Govindarajan A, Tonegawa S (2004) Translational regulatory mechanisms in persistent forms of synaptic plasticity. Neuron 44(1):59–73

    CAS  PubMed  Google Scholar 

  • Kelleher RJ, Geigenmüller U, Hovhannisyan H, Trautman E, Pinard R, Rathmell B, Carpenter R, Margulies D (2012) High-throughput sequencing of mGluR signaling pathway genes reveals enrichment of rare variants in autism. PLoS One 7(4):e35003

    CAS  PubMed  Google Scholar 

  • Keller K, Williams C, Wharton P, Paulk M, Bent-Williams A, Gray B, Ward A, Stalker H, Wallace M, Carter R, Zori R (2003) Routine cytogenetic and FISH studies for 17p11/15q11 duplications and subtelomeric rearrangement studies in children with autism spectrum disorders. Am J Hum Genet 117A(2):105–111

    Google Scholar 

  • Kim SA, Kim JH, Park M, Cho IH, Yoo HJ (2007) Family-based association study between GRIK2 polymorphisms and autism spectrum disorders in the Korean trios. Neurosci Res 58(3):332–335

    CAS  PubMed  Google Scholar 

  • King BH, Wright DM, Handen BL, Sikich L, Zimmerman AW, McMahon W, Cantwell E, Davanzo PA, Dourish CT, Dykens EM, Hooper SR, Jaselskis CA, Leventhal BL, Levitt J, Lord C, Lubetsky MJ, Myers SM, Ozonoff S, Shah BG, Snape M, Shernoff EW, Williamson K, Cook EH (2001) Double-blind, placebo-controlled study of amantadine hydrochloride in the treatment of children with autistic disorder. J Am Acad Child Adolesc Psychiatry 40(6):658–665

    CAS  PubMed  Google Scholar 

  • Klink A, Schiebel K, Winkelmann M, Rao E, Horsthemke B, Lüdecke HJ, Claussen U, Scherer G, Rappold G (1995) The human protein kinase gene PKX1 on Xp22.3 displays Xp/Yp homology and is a site of chromosomal instability. Hum Mol Genet 4(5):869–878

    CAS  PubMed  Google Scholar 

  • Kong A, Frigge ML, Masson G, Besenbacher S, Sulem P, Magnusson G, Gudjonsson SA, Sigurdsson A, Jonasdottir A, Jonasdottir A, Wong WS, Sigurdsson G, Walters GB, Steinberg S, Helgason H, Thorleifsson G, Gudbjartsson DF, Helgason A, Magnusson OT, Thorsteinsdottir U, Stefansson K (2012) Rate of de novo mutations and the importance of father’s age to disease risk. Nature 488(7412):471–475

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kumar RA, KaraMohamed S, Sudi J, Conrad DF, Brune C, Badner JA, Gilliam TC, Nowak NJ, Cook EH, Dobyns WB, Christian SL (2008) Recurrent 16p11.2 microdeletions in autism. Hum Mol Genet 17(4):628–638

    CAS  PubMed  Google Scholar 

  • Kumar RA, Marshall CR, Badner JA, Babatz TD, Mukamel Z, Aldinger KA, Sudi J, Brune CW, Goh G, KaraMohamed S, Sutcliffe JS, Cook EH, Geschwind DH, Dobyns WB, Scherer SW, Christian SL, Reif A (2009) Association and mutation analyses of 16p11.2 autism candidate genes. PLoS One 4(2):e4582

    PubMed Central  PubMed  Google Scholar 

  • Lamb JA, Barnby G, Bonora E, Sykes N, Bacchelli E, Blasi F, Maestrini E, Broxholme J, Tzenova J, Weeks D, Bailey AJ, Monaco AP (2005) Analysis of IMGSAC autism susceptibility loci. Evidence for sex limited and parent of origin specific effects. J Med Genet 42(2):132–137

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lauritsen MB, Als TD, Dahl HA, Flint TJ, Wang AG, Vang M, Kruse TA, Ewald H, Mors O (2006) A genome-wide search for alleles and haplotypes associated with autism and related pervasive developmental disorders on the Faroe Islands. Mol Psychiatry 11(1):37–46

    CAS  PubMed  Google Scholar 

  • Leblond CS, Heinrich J, Delorme R, Proepper C, Betancur C, Huguet G, Konyukh M, Chaste P, Ey E, Rastam M, Anckarsäter H, Nygren G, Gillberg IC, Melke J, Toro R, Regnault B, Fauchereau F, Mercati O, Lemière N, Skuse D, Poot M, Holt R, Monaco AP, Järvelä I, Kantojärvi K, Vanhala R, Curran S, Collier DA, Bolton P, Chiocchetti A, Klauck SM, Poustka F, Freitag CM, Waltes R, Kopp M, Duketis E, Bacchelli E, Minopoli F, Ruta L, Battaglia A, Mazzone L, Maestrini E, Sequeira AF, Oliveira B, Vicente A, Oliveira G, Pinto D, Scherer SW, Zelenika D, Delepine M, Lathrop M, Bonneau D, Guinchat V, Devillard F, Assouline B, Mouren M, Leboyer M, Gillberg C, Boeckers TM, Bourgeron T (2012) Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders. PLoS Genet 8(2):e1002521

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lesch KP, Merker S, Reif A, Novak M (2013) Dances with black widow spiders: dysregulation of glutamate signalling enters centre stage in ADHD. Eur Neuropsychopharmacol 23(6):479–491

    CAS  PubMed  Google Scholar 

  • Levy D, Ronemus M, Yamrom B, Lee Y, Leotta A, Kendall J, Marks S, Lakshmi B, Pai D, Ye K, Buja A, Krieger A, Yoon S, Troge J, Rodgers L, Iossifov I, Wigler M (2011) Rare de novo and transmitted copy-number variation in autistic spectrum disorders. Neuron 70(5):886–897

    CAS  PubMed  Google Scholar 

  • Li H, Zhong X, Chau KF, Williams EC, Chang Q (2011) Loss of activity-induced phosphorylation of MeCP2 enhances synaptogenesis. LTP and spatial memory. Nat Neurosci 14(8):1001–1008

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lichtenstein P, Carlström E, Råstam M, Gillberg C, Anckarsäter H (2010) The genetics of autism spectrum disorders and related neuropsychiatric disorders in childhood. Am J Psychiatry 167(11):1357–1363

    PubMed  Google Scholar 

  • Liu J, Nyholt DR, Magnussen P, Parano E, Pavone P, Geschwind D, Lord C, Iversen P, Hoh J, Ott J, Gilliam TC (2001) A genomewide screen for autism susceptibility loci. Am J Hum Genet 69(2):327–340

    CAS  PubMed Central  PubMed  Google Scholar 

  • Loat CS, Curran S, Lewis CM, Duvall J, Geschwind D, Bolton P, Craig IW (2008) Methyl-CpG-binding protein 2 polymorphisms and vulnerability to autism. Genes Brain Behav 7(7):754–760

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lüscher C, Huber KM (2010) Group 1 mGluR-dependent synaptic long-term depression: mechanisms and implications for circuitry and disease. Neuron 65(4):445–459

    PubMed Central  PubMed  Google Scholar 

  • Ma DQ, Cuccaro ML, Jaworski JM, Haynes CS, Stephan DA, Parod J, Abramson RK, Wright HH, Gilbert JR, Haines JL, Pericak-Vance MA (2007) Dissecting the locus heterogeneity of autism. Significant linkage to chromosome 12q14. Mol Psychiatry 12(4):376–384

    CAS  PubMed  Google Scholar 

  • Mackenzie B, Erickson JD (2004) Sodium-coupled neutral amino acid (System N/A) transporters of the SLC38 gene family. Pflugers Arch 447(5):784–795

    CAS  PubMed  Google Scholar 

  • Malenka RC, Bear MF (2004) LTP and LTD. Neuron 44(1):5–21

    CAS  PubMed  Google Scholar 

  • Marshall CR, Noor A, Vincent JB, Lionel AC, Feuk L, Skaug J, Shago M, Moessner R, Pinto D, Ren Y, Thiruvahindrapduram B, Fiebig A, Schreiber S, Friedman J, Ketelaars CEJ, Vos YJ, Ficicioglu C, Kirkpatrick S, Nicolson R, Sloman L, Summers A, Gibbons CA, Teebi A, Chitayat D, Weksberg R, Thompson A, Vardy C, Crosbie V, Luscombe S, Baatjes R, Zwaigenbaum L, Roberts W, Fernandez B, Szatmari P, Scherer SW (2008) Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet 82(2):477–488

    CAS  PubMed Central  PubMed  Google Scholar 

  • McCauley JL, Li C, Jiang L, Olson LM, Crockett G, Gainer K, Folstein SE, Haines JL, Sutcliffe JS (2005) Genome-wide and ordered-subset linkage analyses provide support for autism loci on 17q and 19p with evidence of phenotypic and interlocus genetic correlates. BMC Med Genet 6:1

    PubMed Central  PubMed  Google Scholar 

  • Mehta MV, Gandal MJ, Siegel SJ (2011) mGluR5-antagonist mediated reversal of elevated stereotyped, repetitive behaviors in the VPA model of autism. PLoS One 6(10):e26077

    CAS  PubMed Central  PubMed  Google Scholar 

  • Miller DT, Shen Y, Weiss LA, Korn J, Anselm I, Bridgemohan C, Cox GF, Dickinson H, Gentile J, Harris DJ, Hegde V, Hundley R, Khwaja O, Kothare S, Luedke C, Nasir R, Poduri A, Prasad K, Raffalli P, Reinhard A, Smith SE, Sobeih MM, Soul JS, Stoler J, Takeoka M, Tan WH, Thakuria J, Wolff R, Yusupov R, Gusella JF, Daly MJ, Wu BL (2009) Microdeletion/duplication at 15q13.2q13.3 among individuals with features of autism and other neuropsychiatric disorders. J Med Genet 46(4):242–248

    CAS  PubMed Central  PubMed  Google Scholar 

  • Moessner R, Marshall CR, Sutcliffe JS, Skaug J, Pinto D, Vincent J, Zwaigenbaum L, Fernandez B, Roberts W, Szatmari P, Scherer SW (2007) Contribution of SHANK3 mutations to autism spectrum disorder. Am J Hum Genet 81(6):1289–1297

    CAS  PubMed Central  PubMed  Google Scholar 

  • Moreno-Fuenmayor H, Borjas L, Arrieta A, Valera V, Socorro-Candanoza L (1996) Plasma excitatory amino acids in autism. Invest Clin 37(2):113–128

    CAS  PubMed  Google Scholar 

  • Mount RH, Charman T, Hastings RP, Reilly S, Cass H (2003) Features of autism in Rett syndrome and severe mental retardation. J Autism Dev Disord 33(4):435–442

    PubMed  Google Scholar 

  • Myers RA, Casals F, Gauthier J, Hamdan FF, Keebler J, Boyko AR, Bustamante CD, Piton AM, Spiegelman D, Henrion E, Zilversmit M, Hussin J, Quinlan J, Yang Y, Lafrenière RG, Griffing AR, Stone EA, Rouleau GA, Awadalla P (2011) A population genetic approach to mapping neurological disorder genes using deep resequencing. PLoS Genet 7(2):e1001318

    CAS  PubMed Central  PubMed  Google Scholar 

  • Neale BM, Kou Y, Liu L, Ma’ayan A, Samocha KE, Sabo A, Lin C, Stevens C, Wang L, Makarov V, Polak P, Yoon S, Maguire J, Crawford EL, Campbell NG, Geller ET, Valladares O, Schafer C, Liu H, Zhao T, Cai G, Lihm J, Dannenfelser R, Jabado O, Peralta Z, Nagaswamy U, Muzny D, Reid JG, Newsham I, Wu Y, Lewis L, Han Y, Voight BF, Lim E, Rossin E, Kirby A, Flannick J, Fromer M, Shakir K, Fennell T, Garimella K, Banks E, Poplin R, Gabriel S, DePristo M, Wimbish JR, Boone BE, Levy SE, Betancur C, Sunyaev S, Boerwinkle E, Buxbaum JD, Cook EH Jr, Devlin B, Gibbs RA, Roeder K, Schellenberg GD, Sutcliffe JS, Daly MJ, Ma’ayan A, Cook EH (2012) Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485(7397):242–245

    CAS  PubMed Central  PubMed  Google Scholar 

  • Nelson TH, Jung J, Deluca TF, Hinebaugh BK, St Gabriel KC, Wall DP (2012) Autworks: a cross-disease network biology application for Autism and related disorders. BMC Med Genomics 5:56

    PubMed Central  PubMed  Google Scholar 

  • Neves-Pereira M, Muller B, Massie D, Williams JHG, O’Brien PCM, Hughes A, Shen S, Clair DS, Miedzybrodzka Z (2009) Deregulation of EIF4E: a novel mechanism for autism. J Med Genet 46(11):759–765

    CAS  PubMed  Google Scholar 

  • Newsholme P, Procopio J, Lima MM, Pithon-Curi TC, Curi R (2003) Glutamine and glutamate—their central role in cell metabolism and function. Cell Biochem Funct 21(1):1–9

    CAS  PubMed  Google Scholar 

  • Nicoll RA, Roche KW (2013) Long-term potentiation: peeling the onion. Neuropharmacology 74:18–22

    CAS  PubMed  Google Scholar 

  • Niklasson L, Rasmussen P, Oskarsdóttir S, Gillberg C (2002) Chromosome 22q11 deletion syndrome (CATCH 22): neuropsychiatric and neuropsychological aspects. Dev Med Child Neurol 44(1):44–50

    PubMed  Google Scholar 

  • Nishimura Y, Martin CL, Vazquez-Lopez A, Spence SJ, Alvarez-Retuerto AI, Sigman M, Steindler C, Pellegrini S, Schanen NC, Warren ST, Geschwind DH (2007) Genome-wide expression profiling of lymphoblastoid cell lines distinguishes different forms of autism and reveals shared pathways. Hum Mol Genet 16(14):1682–1698

    CAS  PubMed  Google Scholar 

  • Nord AS, Roeb W, Dickel DE, Walsh T, Kusenda M, O’Connor KL, Malhotra D, McCarthy SE, Stray SM, Taylor SM, Sebat J, King B, King M, McClellan JM (2011) Reduced transcript expression of genes affected by inherited and de novo CNVs in autism. Eur J Hum Genet 19(6):727–731

    CAS  PubMed Central  PubMed  Google Scholar 

  • O’Roak BJ, Deriziotis P, Lee C, Vives L, Schwartz JJ, Girirajan S, Karakoc E, Mackenzie AP, Ng SB, Baker C, Rieder MJ, Nickerson DA, Bernier R, Fisher SE, Shendure J, Eichler EE (2011) Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations. Nat Genet 43(6):585–589

    PubMed Central  PubMed  Google Scholar 

  • O’Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP, Levy R, Ko A, Lee C, Smith JD, Turner EH, Stanaway IB, Vernot B, Malig M, Baker C, Reilly B, Akey JM, Borenstein E, Rieder MJ, Nickerson DA, Bernier R, Shendure J, Eichler EE (2012) Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485(7397):246–250

    PubMed Central  PubMed  Google Scholar 

  • Owley T, Salt J, Guter S, Grieve A, Walton L, Ayuyao N, Leventhal BL, Cook EH (2006) A prospective, open-label trial of memantine in the treatment of cognitive, behavioral, and memory dysfunction in pervasive developmental disorders. J Child Adolesc Psychopharmacol 16(5):517–524

    PubMed  Google Scholar 

  • Ozgen HM, van Daalen E, Bolton PF, Maloney VK, Huang S, Cresswell L, van den Boogaard MJ, Eleveld MJ, van ‘t Slot R, Hochstenbach R, Beemer FA, Barrow M, Barber JCK, Poot M (2009) Copy number changes of the microcephalin 1 gene (MCPH1) in patients with autism spectrum disorders. Clin Genet 76(4):348–356

    CAS  PubMed  Google Scholar 

  • Pacey LKK, Doss L, Cifelli C, van der Kooy Derek, Heximer SP, Hampson DR (2011) Genetic deletion of regulator of G-protein signaling 4 (RGS4) rescues a subset of fragile X related phenotypes in the FMR1 knockout mouse. Mol Cell Neurosci 46(3):563–572

    CAS  PubMed  Google Scholar 

  • Papanikolaou K, Paliokosta E, Gyftodimou J, Kolaitis G, Vgenopoulou S, Sarri C, Tsiantis J (2006) A case of partial trisomy of chromosome 8p associated with autism. J Autism Dev Disord 36(5):705–709

    PubMed  Google Scholar 

  • Pescucci C, Meloni I, Bruttini M, Ariani F, Longo I, Mari F, Canitano R, Hayek G, Zappella M, Renieri A (2003) Chromosome 2 deletion encompassing the MAP2 gene in a patient with autism and Rett-like features. Clin Genet 64(6):497–501

    CAS  PubMed  Google Scholar 

  • Philippe A, Martinez M, Guilloud-Bataille M, Gillberg C, Rastam M, Sponheim E, Coleman M, Zappella M, Aschauer H, van Maldergem L, Penet C, Feingold J, Brice A, Leboyer M, van Malldergerme L (1999) Genome-wide scan for autism susceptibility genes. Paris Autism Research International Sibpair Study. Hum Mol Genet 8(5):805–812

    CAS  PubMed  Google Scholar 

  • Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D, Regan R, Conroy J, Magalhaes TR, Correia C, Abrahams BS, Almeida J, Bacchelli E, Bader GD, Bailey AJ, Baird G, Battaglia A, Berney T, Bolshakova N, Bölte S, Bolton PF, Bourgeron T, Brennan S, Brian J, Bryson SE, Carson AR, Casallo G, Casey J, Chung BH, Cochrane L, Corsello C, Crawford EL, Crossett A, Cytrynbaum C, Dawson G, de Jonge M, Delorme R, Drmic I, Duketis E, Duque F, Estes A, Farrar P, Fernandez BA, Folstein SE, Fombonne E, Freitag CM, Gilbert J, Gillberg C, Glessner JT, Goldberg J, Green A, Green J, Guter SJ, Hakonarson H, Heron EA, Hill M, Holt R, Howe JL, Hughes G, Hus V, Igliozzi R, Kim C, Klauck SM, Kolevzon A, Korvatska O, Kustanovich V, Lajonchere CM, Lamb JA, Laskawiec M, Leboyer M, Le Couteur A, Leventhal BL, Lionel AC, Liu X, Lord C, Lotspeich L, Lund SC, Maestrini E, Mahoney W, Mantoulan C, Marshall CR, McConachie H, McDougle CJ, McGrath J, McMahon WM, Merikangas A, Migita O, Minshew NJ, Mirza GK, Munson J, Nelson SF, Noakes C, Noor A, Nygren G, Oliveira G, Papanikolaou K, Parr JR, Parrini B, Paton T, Pickles A, Pilorge M, Piven J, Ponting CP, Posey DJ, Poustka A, Poustka F, Prasad A, Ragoussis J, Renshaw K, Rickaby J, Roberts W, Roeder K, Roge B, Rutter ML, Bierut LJ, Rice JP, Salt J, Sansom K, Sato D, Segurado R, Sequeira AF, Senman L, Shah N, Sheffield VC, Soorya L, Sousa I, Stein O, Sykes N, Stoppioni V, Strawbridge C, Tancredi R, Tansey K, Thiruvahindrapduram B, Thompson AP, Thomson S, Tryfon A, Tsiantis J, van Engeland H, Vincent JB, Volkmar F, Wallace S, Wang K, Wang Z, Wassink TH, Webber C, Weksberg R, Wing K, Wittemeyer K, Wood S, Wu J, Yaspan BL, Zurawiecki D, Zwaigenbaum L, Buxbaum JD, Cantor RM, Cook EH, Coon H, Cuccaro ML, Devlin B, Ennis S, Gallagher L, Geschwind DH, Gill M, Haines JL, Hallmayer J, Miller J, Monaco AP, Nurnberger JI Jr, Paterson AD, Pericak-Vance MA, Schellenberg GD, Szatmari P, Vicente AM, Vieland VJ, Wijsman EM, Scherer SW, Sutcliffe JS, Betancur C (2010) Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466(7304):368–372

    CAS  PubMed Central  PubMed  Google Scholar 

  • Piton A, Gauthier J, Hamdan FF, Lafrenière RG, Yang Y, Henrion E, Laurent S, Noreau A, Thibodeau P, Karemera L, Spiegelman D, Kuku F, Duguay J, Destroismaisons L, Jolivet P, Côté M, Lachapelle K, Diallo O, Raymond A, Marineau C, Champagne N, Xiong L, Gaspar C, Rivière J, Tarabeux J, Cossette P, Krebs M, Rapoport JL, Addington A, Delisi LE, Mottron L, Joober R, Fombonne E, Drapeau P, Rouleau GA (2011) Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia. Mol Psychiatry 16(8):867–880

    CAS  PubMed Central  PubMed  Google Scholar 

  • Poelmans G, Franke B, Pauls DL, Glennon JC, Buitelaar JK (2013) AKAPs integrate genetic findings for autism spectrum disorders. Transl Psychiatry 3(6):e270

    CAS  PubMed Central  PubMed  Google Scholar 

  • Prasad C, Prasad AN, Chodirker BN, Lee C, Dawson AK, Jocelyn LJ, Chudley AE (2000) Genetic evaluation of pervasive developmental disorders: the terminal 22q13 deletion syndrome may represent a recognizable phenotype. Clin Genet 57(2):103–109

    CAS  PubMed  Google Scholar 

  • Prather P, de Vries PJ (2004) Behavioral and cognitive aspects of tuberous sclerosis complex. J Child Neurol 19(9):666–674

    PubMed  Google Scholar 

  • Ramanathan S, Woodroffe A, Flodman PL, Mays LZ, Hanouni M, Modahl CB, Steinberg-Epstein R, Bocian ME, Spence MA, Smith M (2004) A case of autism with an interstitial deletion on 4q leading to hemizygosity for genes encoding for glutamine and glycine neurotransmitter receptor sub-units (AMPA 2, GLRA3, GLRB) and neuropeptide receptors NPY1R, NPY5R. BMC Med Genet 5(1):10

    PubMed Central  PubMed  Google Scholar 

  • Ramelli GP, Silacci C, Ferrarini A, Cattaneo C, Visconti P, Pescia G (2008) Microduplication 22q11.2 in a child with autism spectrum disorder: clinical and genetic study. Dev Med Child Neurol 50(12):953–955

    PubMed  Google Scholar 

  • Raught B, Gingras AC (1999) eIF4E activity is regulated at multiple levels. Int J Biochem Cell Biol 31(1):43–57

    CAS  PubMed  Google Scholar 

  • Raynaud F, Janossy A, Dahl J, Bertaso F, Perroy J, Varrault A, Vidal M, Worley PF, Boeckers TM, Bockaert J, Marin P, Fagni L, Homburger V (2013) Shank3–Rich2 interaction regulates AMPA receptor recycling and synaptic long-term potentiation. J Neurosci 33(23):9699–9715

    CAS  PubMed  Google Scholar 

  • Rehnström K, Ylisaukko-oja T, Nummela I, Ellonen P, Kempas E, Vanhala R, von Wendt L, Järvelä I, Peltonen L (2009) Allelic variants in HTR3C show association with autism. Am J Med Genet B Neuropsychiatr Genet 150B(5):741–746

    PubMed Central  PubMed  Google Scholar 

  • Risch N, Spiker D, Lotspeich L, Nouri N, Hinds D, Hallmayer J, Kalaydjieva L, McCague P, Dimiceli S, Pitts T, Nguyen L, Yang J, Harper C, Thorpe D, Vermeer S, Young H, Hebert J, Lin A, Ferguson J, Chiotti C, Wiese-Slater S, Rogers T, Salmon B, Nicholas P, Myers RM et al (1999) A genomic screen of autism. Evidence for a multilocus etiology. Am J Hum Genet 65(2):493–507

    CAS  PubMed Central  PubMed  Google Scholar 

  • Roubertie A, Semprino M, Chaze AM, Rivier F, Humbertclaude V, Cheminal R, Lefort G, Echenne B (2001) Neurological presentation of three patients with 22q11 deletion (CATCH 22 syndrome). Brain Dev 23(8):810–814

    CAS  PubMed  Google Scholar 

  • Sahoo T, Shaw CA, Young AS, Whitehouse NL, Schroer RJ, Stevenson RE, Beaudet AL (2005) Array-based comparative genomic hybridization analysis of recurrent chromosome 15q rearrangements. Am J Med Genet A 139A(2):106–113

    CAS  PubMed  Google Scholar 

  • Sakamoto K, Karelina K, Obrietan K (2011) CREB: a multifaceted regulator of neuronal plasticity and protection. J Neurochem 116(1):1–9

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sanders SJ, Ercan-Sencicek AG, Hus V, Luo R, Murtha MT, Moreno-De-Luca D, Chu SH, Moreau MP, Gupta AR, Thomson SA, Mason CE, Bilguvar K, Celestino-Soper PBS, Choi M, Crawford EL, Davis L, Wright NRD, Dhodapkar RM, DiCola M, DiLullo NM, Fernandez TV, Fielding-Singh V, Fishman DO, Frahm S, Garagaloyan R, Goh GS, Kammela S, Klei L, Lowe JK, Lund SC, McGrew AD, Meyer KA, Moffat WJ, Murdoch JD, O’Roak BJ, Ober GT, Pottenger RS, Raubeson MJ, Song Y, Wang Q, Yaspan BL, Yu TW, Yurkiewicz IR, Beaudet AL, Cantor RM, Curland M, Grice DE, Günel M, Lifton RP, Mane SM, Martin DM, Shaw CA, Sheldon M, Tischfield JA, Walsh CA, Morrow EM, Ledbetter DH, Fombonne E, Lord C, Martin CL, Brooks AI, Sutcliffe JS, Cook EH, Geschwind D, Roeder K, Devlin B, State MW (2011) Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron 70(5):863–885

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, Ercan-Sencicek AG, DiLullo NM, Parikshak NN, Stein JL, Walker MF, Ober GT, Teran NA, Song Y, El-Fishawy P, Murtha RC, Choi M, Overton JD, Bjornson RD, Carriero NJ, Meyer KA, Bilguvar K, Mane SM, Šestan N, Lifton RP, Günel M, Roeder K, Geschwind DH, Devlin B, State MW, Sestan N (2012) De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485(7397):237–241

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sanlaville D, Etchevers HC, Gonzales M, Martinovic J, Clément-Ziza M, Delezoide A, Aubry M, Pelet A, Chemouny S, Cruaud C, Audollent S, Esculpavit C, Goudefroye G, Ozilou C, Fredouille C, Joye N, Morichon-Delvallez N, Dumez Y, Weissenbach J, Munnich A, Amiel J, Encha-Razavi F, Lyonnet S, Vekemans M, Attié-Bitach T (2006) Phenotypic spectrum of CHARGE syndrome in fetuses with CHD7 truncating mutations correlates with expression during human development. J Med Genet 43(3):211–217

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sarbassov DD, Ali SM, Kim D, Guertin DA, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM (2004) Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol 14(14):1296–1302

    CAS  PubMed  Google Scholar 

  • Sato D, Lionel AC, Leblond CS, Prasad A, Pinto D, Walker S, O’Connor I, Russell C, Drmic IE, Hamdan FF, Michaud JL, Endris V, Roeth R, Delorme R, Huguet G, Leboyer M, Rastam M, Gillberg C, Lathrop M, Stavropoulos DJ, Anagnostou E, Weksberg R, Fombonne E, Zwaigenbaum L, Fernandez BA, Roberts W, Rappold GA, Marshall CR, Bourgeron T, Szatmari P, Scherer SW (2012) SHANK1 deletions in males with autism spectrum disorder. Am J Hum Genet 90(5):879–887

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sauter S, von Beust G, Burfeind P, Weise A, Starke H, Liehr T, Zoll B (2003) Autistic disorder and chromosomal mosaicism 46, XY[123]/46, XY, del(20)(pter → p12.2)[10]. Am J Med Genet A 120(4):533–536

    Google Scholar 

  • Schellenberg GD, Dawson G, Sung YJ, Estes A, Munson J, Rosenthal E, Rothstein J, Flodman P, Smith M, Coon H, Leong L, Yu CE, Stodgell C, Rodier PM, Spence MA, Minshew N, McMahon WM, Wijsman EM (2006) Evidence for multiple loci from a genome scan of autism kindreds. Mol Psychiatry 11(11):1049–1060

    Google Scholar 

  • Schorry EK, Keddache M, Lanphear N, Rubinstein JH, Srodulski S, Fletcher D, Blough-Pfau RI, Grabowski GA (2008) Genotype-phenotype correlations in Rubinstein–Taybi syndrome. Am J Med Genet A 146A(19):2512–2519

    CAS  PubMed  Google Scholar 

  • Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, Walsh T, Yamrom B, Yoon S, Krasnitz A, Kendall J, Leotta A, Pai D, Zhang R, Lee YH, Hicks J, Spence SJ, Lee AT, Puura K, Lehtimaki T, Ledbetter D, Gregersen PK, Bregman J, Sutcliffe JS, Jobanputra V, Chung W, Warburton D, King MC, Skuse D, Geschwind DH, Gilliam TC, Ye K, Wigler M (2007) Strong association of de novo copy number mutations with autism. Science 316(5823):445–449

    CAS  PubMed Central  PubMed  Google Scholar 

  • Serajee FJ, Mahbubul Huq AHM (2009) Association of Y chromosome haplotypes with autism. J Child Neurol 24(10):1258–1261

    PubMed  Google Scholar 

  • Serajee FJ, Zhong H, Nabi R, Huq AHM (2003) The metabotropic glutamate receptor 8 gene at 7q31: partial duplication and possible association with autism. J. Med. Genet 40(4):e42

    CAS  PubMed Central  PubMed  Google Scholar 

  • Shen Y, Dies KA, Holm IA, Bridgemohan C, Sobeih MM, Caronna EB, Miller KJ, Frazier JA, Silverstein I, Picker J, Weissman L, Raffalli P, Jeste S, Demmer LA, Peters HK, Brewster SJ, Kowalczyk SJ, Rosen-Sheidley B, McGowan C, Duda AW, Lincoln SA, Lowe KR, Schonwald A, Robbins M, Hisama F, Wolff R, Becker R, Nasir R, Urion DK, Milunsky JM, Rappaport L, Gusella JF, Walsh CA, Wu B, Miller DT (2010) Clinical genetic testing for patients with autism spectrum disorders. Pediatrics 125(4):e727–e735

    PubMed  Google Scholar 

  • Shigemoto R, Kinoshita A, Wada E, Nomura S, Ohishi H, Takada M, Flor PJ, Neki A, Abe T, Nakanishi S, Mizuno N (1997) Differential presynaptic localization of metabotropic glutamate receptor subtypes in the rat hippocampus. J Neurosci 17(19):7503–7522

    CAS  PubMed  Google Scholar 

  • Shinohe A, Hashimoto K, Nakamura K, Tsujii M, Iwata Y, Tsuchiya KJ, Sekine Y, Suda S, Suzuki K, Sugihara G, Matsuzaki H, Minabe Y, Sugiyama T, Kawai M, Iyo M, Takei N, Mori N (2006) Increased serum levels of glutamate in adult patients with autism. Prog Neuropsychopharmacol Biol Psychiatry 30(8):1472–1477

    CAS  PubMed  Google Scholar 

  • Shuang M, Liu J, Jia MX, Yang JZ, Wu SP, Gong XH, Ling YS, Ruan Y, Yang XL, Zhang D (2004) Family-based association study between autism and glutamate receptor 6 gene in Chinese Han trios. Am J Med Genet B Neuropsychiatr Genet 131B(1):48–50

    PubMed  Google Scholar 

  • Sihra TS, Flores G, Rodríguez-Moreno A (2013) Kainate receptors: multiple roles in neuronal plasticity. Neuroscientist 20:29–43

    PubMed  Google Scholar 

  • Silva AE, Vayego-Lourenco SA, Fett-Conte AC, Goloni-Bertollo EM, Varella-Garcia M (2002) Tetrasomy 15q11–q13 identified by fluorescence in situ hybridization in a patient with autistic disorder. Arq Neuropsiquiatr 60(2-A):290–294

    PubMed  Google Scholar 

  • Soysal Y, Vermeesch J, Davani NA, Hekimler K, Imirzalioğlu N (2011) A 10.46 Mb 12p11.1–12.1 interstitial deletion coincident with a 0.19 Mb NRXN1 deletion detected by array CGH in a girl with scoliosis and autism. Am J Med Genet A 155A(7):1745–1752

    PubMed  Google Scholar 

  • Spence SJ, Cantor RM, Chung L, Kim S, Geschwind DH, Alarcón M (2006) Stratification based on language-related endophenotypes in autism: attempt to replicate reported linkage. Am J Med Genet B Neuropsychiatr Genet 141B(6):591–598

    PubMed  Google Scholar 

  • Szatmari P, Paterson AD, Zwaigenbaum L, Roberts W, Brian J, Liu X, Vincent JB, Skaug JL, Thompson AP, Senman L, Feuk L, Qian C, Bryson SE, Jones MB, Marshall CR, Scherer SW, Vieland VJ, Bartlett C, Mangin LV, Goedken R, Segre A, Pericak-Vance MA, Cuccaro ML, Gilbert JR, Wright HH, Abramson RK, Betancur C, Bourgeron T, Gillberg C, Leboyer M, Buxbaum JD, Davis KL, Hollander E, Silverman JM, Hallmayer J, Lotspeich L, Sutcliffe JS, Haines JL, Folstein SE, Piven J, Wassink TH, Sheffield V, Geschwind DH, Bucan M, Brown WT, Cantor RM, Constantino JN, Gilliam TC, Herbert M, LaJonchere C, Ledbetter DH, Lese-Martin C, Miller J, Nelson S, Samango-Sprouse CA, Spence S, State M, Tanzi RE, Coon H, Dawson G, Devlin B, Estes A, Flodman P, Klei L, McMahon WM, Minshew N, Munson J, Korvatska E, Rodier PM, Schellenberg GD, Smith M, Spence MA, Stodgell C, Tepper PG, Wijsman EM, Yu C, Rogé B, Mantoulan C, Wittemeyer K, Poustka A, Felder B, Klauck SM, Schuster C, Poustka F, Bölte S, Feineis-Matthews S, Herbrecht E, Schmötzer G, Tsiantis J, Papanikolaou K, Maestrini E, Bacchelli E, Blasi F, Carone S, Toma C, van Engeland H, de Jonge M, Kemner C, Koop F, Langemeijer M, Hijimans C, Staal WG, Baird G, Bolton PF, Rutter ML, Weisblatt E, Green J, Aldred C, Wilkinson J, Pickles A, Le Couteur A, Berney T, McConachie H, Bailey AJ, Francis K, Honeyman G, Hutchinson A, Parr JR, Wallace S, Monaco AP, Barnby G, Kobayashi K, Lamb JA, Sousa I, Sykes N, Cook EH, Guter SJ, Leventhal BL, Salt J, Lord C, Corsello C, Hus V, Weeks DE, Volkmar F, Tauber M, Fombonne E, Shih A, Koop F, Langemeijer M, Hijmans C, Meyer KJ (2007) Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet 39(3):319–328

    CAS  PubMed  Google Scholar 

  • Takayasu Y, Iino M, Takatsuru Y, Tanaka K, Ozawa S (2009) Functions of glutamate transporters in cerebellar Purkinje cell synapses. Acta Physiol (Oxf) 197(1):1–12

    CAS  Google Scholar 

  • Thomas NS, Sharp AJ, Browne CE, Skuse D, Hardie C, Dennis NR (1999) Xp deletions associated with autism in three females. Hum Genet 104(1):43–48

    CAS  PubMed  Google Scholar 

  • Thomas AM, Bui N, Perkins JR, Yuva-Paylor LA, Paylor R (2012) Group I metabotropic glutamate receptor antagonists alter select behaviors in a mouse model for fragile X syndrome. Psychopharmacology 219(1):47–58

    CAS  PubMed  Google Scholar 

  • Tidyman WE, Rauen KA (2009) The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation. Curr Opin Genet Dev 19(3):230–236

    CAS  PubMed Central  PubMed  Google Scholar 

  • Toma C, Torrico B, Hervás A, Valdés-Mas R, Tristán-Noguero A, Padillo V, Maristany M, Salgado M, Arenas C, Puente XS, Bayés M, Cormand B (2013) Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations. Mol Psychiatry. [Epub ahead of print]

  • Urraca N, Cleary J, Brewer V, Pivnick EK, McVicar K, Thibert RL, Schanen NC, Esmer C, Lamport D, Reiter LT (2013) The interstitial duplication 15q11.2–q13 syndrome includes autism, mild facial anomalies and a characteristic EEG signature. Autism Res 6(4):268–279

    PubMed Central  PubMed  Google Scholar 

  • van der Zwaag B, Franke L, Poot M, Hochstenbach R, Spierenburg HA, Vorstman JAS, van Daalen E, de Jonge MV, Verbeek NE, Brilstra EH, van ‘t Slot R, Ophoff RA, van Es MA, Blauw HM, Veldink JH, Buizer-Voskamp JE, Beemer FA, van den Berg LH, Wijmenga C, van Amstel HKP, van Engeland H, Burbach JPH, Staal WG (2009) Gene-network analysis identifies susceptibility genes related to glycobiology in autism. PLoS One 4(5):e5324

    PubMed Central  PubMed  Google Scholar 

  • van der Zwaag B, Staal WG, Hochstenbach R, Poot M, Spierenburg HA, de Jonge MV, Verbeek NE, van ‘t Slot R, van Es, Michael A, Staal FJ, Freitag CM, Buizer-Voskamp JE, Nelen MR, van den Berg LH, van Amstel HKP, van Engeland H, Burbach JPH (2010) A co-segregating microduplication of chromosome 15q11.2 pinpoints two risk genes for autism spectrum disorder. Am J Med Genet B Neuropsychiatr Genet 153B(4):960–966

  • Vanhoutte P, Barnier JV, Guibert B, Pagès C, Besson MJ, Hipskind RA, Caboche J (1999) Glutamate induces phosphorylation of Elk-1 and CREB, along with c-fos activation, via an extracellular signal-regulated kinase-dependent pathway in brain slices. Mol Cell Biol 19(1):136–146

    CAS  PubMed Central  PubMed  Google Scholar 

  • Verpelli C, Dvoretskova E, Vicidomini C, Rossi F, Chiappalone M, Schoen M, Di Stefano B, Mantegazza R, Broccoli V, Böckers TM, Dityatev A, Sala C (2011) Importance of Shank3 protein in regulating metabotropic glutamate receptor 5 (mGluR5) expression and signaling at synapses. J Biol Chem 286(40):34839–34850

    CAS  PubMed Central  PubMed  Google Scholar 

  • Vincent JB, Thevarkunnel S, Kolozsvari D, Paterson AD, Roberts W, Scherer SW (2004) Association and transmission analysis of the FMR1 IVS10+14C-T variant in autism. Am J Hum Genet 125B(1):54–56

    Google Scholar 

  • Waltereit R, Weller M (2003) Signaling from cAMP/PKA to MAPK and synaptic plasticity. Mol Neurobiol 27(1):99–106

    CAS  PubMed  Google Scholar 

  • Wang K, Zhang H, Ma D, Bucan M, Glessner JT, Abrahams BS, Salyakina D, Imielinski M, Bradfield JP, Sleiman PMA, Kim CE, Hou C, Frackelton E, Chiavacci R, Takahashi N, Sakurai T, Rappaport E, Lajonchere CM, Munson J, Estes A, Korvatska O, Piven J, Sonnenblick LI, Alvarez Retuerto AI, Herman EI, Dong H, Hutman T, Sigman M, Ozonoff S, Klin A, Owley T, Sweeney JA, Brune CW, Cantor RM, Bernier R, Gilbert JR, Cuccaro ML, McMahon WM, Miller J, State MW, Wassink TH, Coon H, Levy SE, Schultz RT, Nurnberger JI, Haines JL, Sutcliffe JS, Cook EH, Minshew NJ, Buxbaum JD, Dawson G, Grant SFA, Geschwind DH, Pericak-Vance MA, Schellenberg GD, Hakonarson H (2009) Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 459(7246):528–533

    Google Scholar 

  • Wassink TH, Piven J, Patil SR (2001) Chromosomal abnormalities in a clinic sample of individuals with autistic disorder. Psychiatr Genet 11(2):57–63

    CAS  PubMed  Google Scholar 

  • Weinstein LS, Chen M, Liu J (2002) Gs(alpha) mutations and imprinting defects in human disease. Ann N Y Acad Sci 968:173–197

    CAS  PubMed  Google Scholar 

  • Weintraub K (2011) The prevalence puzzle: autism counts. Nature 479(7371):22–24

    CAS  PubMed  Google Scholar 

  • Weiss LA, Shen Y, Korn JM, Arking DE, Miller DT, Fossdal R, Saemundsen E, Stefansson H, Ferreira MAR, Green T, Platt OS, Ruderfer DM, Walsh CA, Altshuler D, Chakravarti A, Tanzi RE, Stefansson K, Santangelo SL, Gusella JF, Sklar P, Wu B, Daly MJ (2008) Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med 358(7):667–675

    CAS  PubMed  Google Scholar 

  • Wolpert CM, Donnelly SL, Cuccaro ML, Hedges DJ, Poole CP, Wright HH, Gilbert JR, Pericak-Vance MA (2001) De novo partial duplication of chromosome 7p in a male with autistic disorder. Am J Med Genet 105(3):222–225

    CAS  PubMed  Google Scholar 

  • Won H, Lee H, Gee HY, Mah W, Kim J, Lee J, Ha S, Chung C, Jung ES, Cho YS, Park S, Lee J, Lee K, Kim D, Bae YC, Kaang B, Lee MG, Kim E (2012) Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function. Nature 486(7402):261–265

    CAS  PubMed  Google Scholar 

  • Wong M, Ess KC, Uhlmann EJ, Jansen LA, Li W, Crino PB, Mennerick S, Yamada KA, Gutmann DH (2003) Impaired glial glutamate transport in a mouse tuberous sclerosis epilepsy model. Ann Neurol 54(2):251–256

    CAS  PubMed  Google Scholar 

  • Wu Y, Arai AC, Rumbaugh G, Srivastava AK, Turner G, Hayashi T, Suzuki E, Jiang Y, Zhang L, Rodriguez J, Boyle J, Tarpey P, Raymond FL, Nevelsteen J, Froyen G, Stratton M, Futreal A, Gecz J, Stevenson R, Schwartz CE, Valle D, Huganir RL, Wang T (2007) Mutations in ionotropic AMPA receptor 3 alter channel properties and are associated with moderate cognitive impairment in humans. Proc Natl Acad Sci USA 104(46):18163–18168

    CAS  PubMed Central  PubMed  Google Scholar 

  • Xu L, Li J, Huang Y, Zhao M, Tang X, Wei L (2011) AutismKB: an evidence-based knowledgebase of autism genetics. Nucleic Acids Res 40(D1):D1016–D1022

    PubMed Central  PubMed  Google Scholar 

  • Ylisaukko-Oja T, Alarcon JM, Cantor RM, Auranen M, Vanhala R, Kempas E, von Wendt L, Jarvela I, Geschwind DH, Peltonen L (2006) Search for autism loci by combined analysis of Autism Genetic Resource Exchange and Finnish families. Ann Neurol 59(1):145–155

    PubMed  Google Scholar 

  • Yonan AL, Alarcon JM, Cheng R, Magnusson PK, Spence SJ, Palmer AA, Grunn A, Juo SH, Terwilliger JD, Liu J, Cantor RM, Geschwind DH, Gilliam TC (2003) A genomewide screen of 345 families for autism-susceptibility loci. Am J Hum Genet 73(4):886–897

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yoo HJ, Cho IH, Park M, Yang SY, Kim SA (2012) Family based association of GRIN2A and GRIN2B with Korean autism spectrum disorders. Neurosci Lett 512(2):89–93

    CAS  PubMed  Google Scholar 

  • Yu CE, Dawson G, Munson J, D’Souza I, Osterling J, Estes A, Leutenegger AL, Flodman P, Smith M, Raskind WH, Spence MA, McMahon W, Wijsman EM, Schellenberg GD (2002) Presence of large deletions in kindreds with autism. Am J Hum Genet 71(1):100–115

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zappella M, Meloni I, Longo I, Canitano R, Hayek G, Rosaia L, Mari F, Renieri A (2003) Study of MECP2 gene in Rett syndrome variants and autistic girls. Am J Hum Genet 119B(1):102–107

    Google Scholar 

  • Zhong X, Li H, Chang Q (2012) MeCP2 phosphorylation is required for modulating synaptic scaling through mGluR5. J Neurosci 32(37):12841–12847

    CAS  PubMed Central  PubMed  Google Scholar 

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  1. Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt, Goethe University, Deutschordenstraße 50, 60528, Frankfurt am Main, Germany

    Andreas G. Chiocchetti, Hanna S. Bour & Christine M. Freitag

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Chiocchetti, A.G., Bour, H.S. & Freitag, C.M. Glutamatergic candidate genes in autism spectrum disorder: an overview. J Neural Transm 121, 1081–1106 (2014). https://doi.org/10.1007/s00702-014-1161-y

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