CNS Drugs

, Volume 29, Issue 6, pp 453–463 | Cite as

Developing Medications Targeting Glutamatergic Dysfunction in Autism: Progress to Date

Leading Article

Abstract

Pharmacologic treatments targeting specific molecular mechanisms relevant for autism spectrum disorder (ASD) are beginning to emerge in early drug development. This article reviews the evidence for the disruption of glutamatergic neurotransmission in animal models of social deficits and summarizes key pre-clinical and clinical efforts in developing pharmacologic interventions based on modulation of glutamatergic systems in individuals with ASD. Understanding the pathobiology of the glutamatergic system has led to the development of new investigational treatments for individuals with ASD. Specific examples of medications that modulate the glutamatergic system in pre-clinical and clinical studies are described. Finally, we discuss the limitations of current strategies and future opportunities in developing medications targeting the glutamatergic system for treating individuals with ASD.

References

  1. 1.
    CDC. Prevalence of autism spectrum disorder among children aged 8 years—autism and developmental disabilities monitoring network, 11 sites, United States, 2010. Morb Mortal Wkly Rep Surveill Summ. 2014;63(Suppl 2):1–21.Google Scholar
  2. 2.
    De Rubeis S, He X, Goldberg AP, Poultney CS, Samocha K, Ercument Cicek A, et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature. 2014;515(7526):209–15.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Rubenstein JL, Merzenich MM. Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav. 2003;2(5):255–67.PubMedCrossRefGoogle Scholar
  4. 4.
    Purcell AE, Jeon OH, Zimmerman AW, Blue ME, Pevsner J. Postmortem brain abnormalities of the glutamate neurotransmitter system in autism. Neurology. 2001;57(9):1618–28.PubMedCrossRefGoogle Scholar
  5. 5.
    Fatemi SH, Folsom TD, Kneeland RE, Liesch SB. Metabotropic glutamate receptor 5 upregulation in children with autism is associated with underexpression of both fragile X mental retardation protein and GABA(A) receptor beta 3 in adults with autism. Anat Rec (Hoboken). 2011;294(10):1635–45.CrossRefGoogle Scholar
  6. 6.
    Aldred S, Moore KM, Fitzgerald M, Waring RH. Plasma amino acid levels in children with autism and their families. J Autism Dev Disord. 2003;33(1):93–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Tirouvanziam R, Obukhanych TV, Laval J, Aronov PA, Libove R, Banerjee AG, et al. Distinct plasma profile of polar neutral amino acids, leucine, and glutamate in children with autism spectrum disorders. J Autism Dev Disord. 2012;42(5):827–36.PubMedCrossRefGoogle Scholar
  8. 8.
    Shimmura C, Suda S, Tsuchiya KJ, Hashimoto K, Ohno K, Matsuzaki H, et al. Alteration of plasma glutamate and glutamine levels in children with high-functioning autism. PLoS One. 2011;6(10):e25340.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Shinohe A, Hashimoto K, Nakamura K, Tsujii M, Iwata Y, Tsuchiya KJ, et al. Increased serum levels of glutamate in adult patients with autism. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30(8):1472–7.PubMedCrossRefGoogle Scholar
  10. 10.
    Page LA, Daly E, Schmitz N, Simmons A, Toal F, Deeley Q, et al. In vivo 1H-magnetic resonance spectroscopy study of amygdala-hippocampal and parietal regions in autism. Am J Psychiatry. 2006;163(12):2189–92.PubMedGoogle Scholar
  11. 11.
    Joshi G, Biederman J, Wozniak J, Goldin RL, Crowley D, Furtak S, et al. Magnetic resonance spectroscopy study of the glutamatergic system in adolescent males with high-functioning autistic disorder: a pilot study at 4T. Eur Arch Psychiatry Clin Neurosci. 2013;263(5):379–84.PubMedCrossRefGoogle Scholar
  12. 12.
    Bejjani A, O’Neill J, Kim JA, Frew AJ, Yee VW, Ly R, et al. Elevated glutamatergic compounds in pregenual anterior cingulate in pediatric autism spectrum disorder demonstrated by 1H MRS and 1H MRSI. PLoS One. 2012;7(7):e38786.PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Brown MS, Singel D, Hepburn S, Rojas DC. Increased glutamate concentration in the auditory cortex of persons with autism and first-degree relatives: a (1)H-MRS study. Autism Res. 2013;6(1):1–10.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Bernardi S, Anagnostou E, Shen J, Kolevzon A, Buxbaum JD, Hollander E, et al. In vivo 1H-magnetic resonance spectroscopy study of the attentional networks in autism. Brain Res. 2011;22(1380):198–205.CrossRefGoogle Scholar
  15. 15.
    Hardan AY, Minshew NJ, Melhem NM, Srihari S, Jo B, Bansal R, et al. An MRI and proton spectroscopy study of the thalamus in children with autism. Psychiatry Res. 2008;163(2):97–105.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Doyle-Thomas KA, Card D, Soorya LV, Wang AT, Fan J, Anagnostou E. Metabolic mapping of deep brain structures and associations with symptomatology in autism spectrum disorders. Res Autism Spectr Disord. 2014;8(1):44–51.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Kubas B, Kulak W, Sobaniec W, Tarasow E, Lebkowska U, Walecki J. Metabolite alterations in autistic children: a 1H MR spectroscopy study. Adv Med Sci. 2012;57(1):152–6.PubMedCrossRefGoogle Scholar
  18. 18.
    Rojas DC. The role of glutamate and its receptors in autism and the use of glutamate receptor antagonists in treatment. J Neural Transm. 2014;121(8):891–905.PubMedCrossRefGoogle Scholar
  19. 19.
    Buttenschon HN, Lauritsen MB, El Daoud A, Hollegaard M, Jorgensen M, Tvedegaard K, et al. A population-based association study of glutamate decarboxylase 1 as a candidate gene for autism. J Neural Transm. 2009;116(3):381–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Chang SC, Pauls DL, Lange C, Sasanfar R, Santangelo SL. Common genetic variation in the GAD1 gene and the entire family of DLX homeobox genes and autism spectrum disorders. Am J Med Genet B Neuropsychiatr Genet. 2011;156(2):233–9.PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    O’Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP, et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature. 2012;485(7397):246–50.PubMedCentralPubMedCrossRefGoogle Scholar
  22. 22.
    Sudhof TC. Neuroligins and neurexins link synaptic function to cognitive disease. Nature. 2008;455(7215):903–11.PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Talebizadeh Z, Bittel DC, Veatch OJ, Butler MG, Takahashi TN, Miles JH. Do known mutations in neuroligin genes (NLGN3 and NLGN4) cause autism? J Autism Dev Disord. 2004;34(6):735–6.PubMedCrossRefGoogle Scholar
  24. 24.
    Gauthier J, Bonnel A, St-Onge J, Karemera L, Laurent S, Mottron L, et al. NLGN3/NLGN4 gene mutations are not responsible for autism in the Quebec population. Am J Med Genet B Neuropsychiatr Genet. 2005;132B(1):74–5.PubMedCrossRefGoogle Scholar
  25. 25.
    Foldy C, Malenka RC, Sudhof TC. Autism-associated neuroligin-3 mutations commonly disrupt tonic endocannabinoid signaling. Neuron. 2013;78(3):498–509.PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Jamain S, Quach H, Betancur C, Rastam M, Colineaux C, Gillberg IC, et al. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat Genet. 2003;34(1):27–9.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Laumonnier F, Bonnet-Brilhault F, Gomot M, Blanc R, David A, Moizard MP, et al. X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family. Am J Hum Genet. 2004;74(3):552–7.PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Autism Genome Project C, Szatmari P, Paterson AD, Zwaigenbaum L, Roberts W, Brian J, et al. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet. 2007;39(3):319–28.CrossRefGoogle Scholar
  29. 29.
    Bremer A, Giacobini M, Eriksson M, Gustavsson P, Nordin V, Fernell E, et al. Copy number variation characteristics in subpopulations of patients with autism spectrum disorders. Am J Med Genet B Neuropsychiatr Genet. 2011;156(2):115–24.PubMedCrossRefGoogle Scholar
  30. 30.
    Pinto D, Pagnamenta AT, Klei L, Anney R, Merico D, Regan R, et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature. 2010;466(7304):368–72.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Gauthier J, Siddiqui TJ, Huashan P, Yokomaku D, Hamdan FF, Champagne N, et al. Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia. Hum Genet. 2011;130(4):563–73.PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Vaags AK, Lionel AC, Sato D, Goodenberger M, Stein QP, Curran S, et al. Rare deletions at the neurexin 3 locus in autism spectrum disorder. Am J Hum Genet. 2012;90(1):133–41.PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Strauss KA, Puffenberger EG, Huentelman MJ, Gottlieb S, Dobrin SE, Parod JM, et al. Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2. N Engl J Med. 2006;354(13):1370–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Bakkaloglu B, O’Roak BJ, Louvi A, Gupta AR, Abelson JF, Morgan TM, et al. Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders. Am J Hum Genet. 2008;82(1):165–73.PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Alarcon M, Abrahams BS, Stone JL, Duvall JA, Perederiy JV, Bomar JM, et al. Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. Am J Hum Genet. 2008;82(1):150–9.PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Sampath S, Bhat S, Gupta S, O’Connor A, West AB, Arking DE, et al. Defining the contribution of CNTNAP2 to autism susceptibility. PLoS One. 2013;8(10):e77906.PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Meyer D, Bonhoeffer T, Scheuss V. Balance and stability of synaptic structures during synaptic plasticity. Neuron. 2014;82(2):430–43.PubMedCrossRefGoogle Scholar
  38. 38.
    Sheng M, Sala C. PDZ domains and the organization of supramolecular complexes. Annu Rev Neurosci. 2001;24:1–29.PubMedCrossRefGoogle Scholar
  39. 39.
    Feyder M, Karlsson RM, Mathur P, Lyman M, Bock R, Momenan R, et al. 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. 2010;167(12):1508–17.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Wellmann KA, Varlinskaya EI, Mooney SM. d-Cycloserine ameliorates social alterations that result from prenatal exposure to valproic acid. Brain Res Bull. 2014;15(108C):1–9.CrossRefGoogle Scholar
  41. 41.
    Deutsch SI, Pepe GJ, Burket JA, Winebarger EE, Herndon AL, Benson AD. d-Cycloserine improves sociability and spontaneous stereotypic behaviors in 4-week old mice. Brain Res. 2012;23(1439):96–107.CrossRefGoogle Scholar
  42. 42.
    Modi ME, Young LJ. d-Cycloserine facilitates socially reinforced learning in an animal model relevant to autism spectrum disorders. Biol Psychiatry. 2011;70(3):298–304.PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Burket JA, Benson AD, Tang AH, Deutsch SI. d-Cycloserine improves sociability in the BTBR T+ Itpr3tf/J mouse model of autism spectrum disorders with altered Ras/Raf/ERK1/2 signaling. Brain Res Bull. 2013;96:62–70.PubMedCrossRefGoogle Scholar
  44. 44.
    Won H, Lee HR, Gee HY, Mah W, Kim JI, Lee J, et al. Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function. Nature. 2012;486(7402):261–5.PubMedCrossRefGoogle Scholar
  45. 45.
    Posey DJ, Kem DL, Swiezy NB, Sweeten TL, Wiegand RE, McDougle CJ. A pilot study of d-cycloserine in subjects with autistic disorder. Am J Psychiatry. 2004;161(11):2115–7.PubMedCrossRefGoogle Scholar
  46. 46.
    Urbano M, Okwara L, Manser P, Hartmann K, Herndon A, Deutsch SI. A trial of d-cycloserine to treat stereotypies in older adolescents and young adults with autism spectrum disorder. Clin Neuropharmacol. 2014;37(3):69–72.PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Pahwa R, Tanner CM, Hauser RA, Sethi K, Isaacson S, Truong D, et al. Amantadine extended release for levodopa-induced dyskinesia in Parkinson’s disease (EASED Study). Mov Disord. 2015;30(6):788–95.PubMedCrossRefGoogle Scholar
  48. 48.
    King BH, Wright DM, Handen BL, Sikich L, Zimmerman AW, McMahon W, et al. Double-blind, placebo-controlled study of amantadine hydrochloride in the treatment of children with autistic disorder. J Am Acad Child Adolesc Psychiatry. 2001;40(6):658–65.PubMedCrossRefGoogle Scholar
  49. 49.
    Wilkinson D, Wirth Y, Goebel C. Memantine in patients with moderate to severe Alzheimer’s disease: meta-analyses using realistic definitions of response. Dement Geriatr Cogn Disord. 2014;37(1–2):71–85.PubMedCrossRefGoogle Scholar
  50. 50.
    Erickson CA, Posey DJ, Stigler KA, Mullett J, Katschke AR, McDougle CJ. A retrospective study of memantine in children and adolescents with pervasive developmental disorders. Psychopharmacology. 2007;191(1):141–7.PubMedCrossRefGoogle Scholar
  51. 51.
    Owley T, Salt J, Guter S, Grieve A, Walton L, Ayuyao N, et al. A prospective, open-label trial of memantine in the treatment of cognitive, behavioral, and memory dysfunction in pervasive developmental disorders. J Child Adolesc Psychopharmacol. 2006;16(5):517–24.PubMedCrossRefGoogle Scholar
  52. 52.
    Forest Laboratories. Safety study of memantine in pediatric patients with autism, Asperger’s disorder or pervasive developmental disorder not otherwise specified (PDD-NOS) [ClinicalTrials.gov identifier NCT01592773]. US National Institutes of Health, ClinicalTrials.gov. 2015. http://www.clinicaltrials.gov. Accessed 29 May 2015.
  53. 53.
    Doble A. The pharmacology and mechanism of action of riluzole. Neurology. 1996;47(6 Suppl 4):S233–41.PubMedCrossRefGoogle Scholar
  54. 54.
    Miller RG, Mitchell JD, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev. 2012;3:CD001447. Accessed May 29 2015.PubMedGoogle Scholar
  55. 55.
    Wink LK, Erickson CA, Stigler KA, McDougle CJ. Riluzole in autistic disorder. J Child Adolesc Psychopharmacol. 2011;21(4):375–9.PubMedCrossRefGoogle Scholar
  56. 56.
    Rosner S, Hackl-Herrwerth A, Leucht S, Lehert P, Vecchi S, Soyka M. Acamprosate for alcohol dependence. Cochrane Database Syst Rev. 2010;9:CD004332.PubMedGoogle Scholar
  57. 57.
    Erickson CA, Wink LK, Early MC, Stiegelmeyer E, Mathieu-Frasier L, Patrick V, et al. Brief report: pilot single-blind placebo lead-in study of acamprosate in youth with autistic disorder. J Autism Dev Disord. 2014;44(4):981–7.PubMedCrossRefGoogle Scholar
  58. 58.
    Angehagen M, Ronnback L, Hansson E, Ben-Menachem E. Topiramate reduces AMPA-induced Ca(2+) transients and inhibits GluR1 subunit phosphorylation in astrocytes from primary cultures. J Neurochem. 2005;94(4):1124–30.PubMedCrossRefGoogle Scholar
  59. 59.
    Hardan AY, Jou RJ, Handen BL. A retrospective assessment of topiramate in children and adolescents with pervasive developmental disorders. J Child Adolesc Psychopharmacol. 2004;14(3):426–32.PubMedCrossRefGoogle Scholar
  60. 60.
    Reiss AL, Dant CC. The behavioral neurogenetics of fragile X syndrome: analyzing gene-brain-behavior relationships in child developmental psychopathologies. Dev Psychopathol. 2003;15(4):927–68.PubMedCrossRefGoogle Scholar
  61. 61.
    Freund LS, Reiss AL. Cognitive profiles associated with the fra(X) syndrome in males and females. Am J Med Genet. 1991;38(4):542–7.PubMedCrossRefGoogle Scholar
  62. 62.
    Hill MK, Archibald AD, Cohen J, Metcalfe SA. A systematic review of population screening for fragile X syndrome. Genet Med. 2010;12(7):396–410.PubMedCrossRefGoogle Scholar
  63. 63.
    Wheeler AC, Mussey J, Villagomez A, Bishop E, Raspa M, Edwards A, et al. DSM-5 changes and the prevalence of parent-reported autism spectrum symptoms in Fragile X syndrome. J Autism Dev Disord. 2015;45(3):816–29.PubMedCrossRefGoogle Scholar
  64. 64.
    Feinstein C, Reiss AL. Autism: the point of view from fragile X studies. J Autism Dev Disord. 1998;28(5):393–405.PubMedCrossRefGoogle Scholar
  65. 65.
    Kau AS, Tierney E, Bukelis I, Stump MH, Kates WR, Trescher WH, et al. Social behavior profile in young males with fragile X syndrome: characteristics and specificity. Am J Med Genet A. 2004;126A(1):9–17.PubMedCrossRefGoogle Scholar
  66. 66.
    Van der Molen MJ, Huizinga M, Huizenga HM, Ridderinkhof KR, Van der Molen MW, Hamel BJ, et al. Profiling fragile X Syndrome in males: strengths and weaknesses in cognitive abilities. Res Dev Disabil. 2010;31(2):426–39.PubMedCrossRefGoogle Scholar
  67. 67.
    Feinstein C, Singh S. Social phenotypes in neurogenetic syndromes. Child Adolesc Psychiatr Clin N Am. 2007;16(3):631–47.PubMedCrossRefGoogle Scholar
  68. 68.
    Gantois I, Pop AS, de Esch CE, Buijsen RA, Pooters T, Gomez-Mancilla B, et al. Chronic administration of AFQ056/Mavoglurant restores social behaviour in Fmr1 knockout mice. Behav Brain Res. 2013;15(239):72–9.CrossRefGoogle Scholar
  69. 69.
    Jacquemont S, Curie A, des Portes V, Torrioli MG, Berry-Kravis E, Hagerman RJ, et al. Epigenetic modification of the FMR1 gene in fragile X syndrome is associated with differential response to the mGluR5 antagonist AFQ056. Sci Transl Med. 2011;3(64):64ra1.PubMedCrossRefGoogle Scholar
  70. 70.
    Jaeschke G, Kolczewski S, Spooren W, Vieira E, Bitter-Stoll N, Boissin P, et al. Metabotropic glutamate receptor 5 negative allosteric modulators: discovery of 2-chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]pyridine (Basimglurant, RO4917523), a promising novel medicine for psychiatric diseases. J Med Chem. 2015;58(3):1358–71.PubMedCrossRefGoogle Scholar
  71. 71.
    Grant JE, Odlaug BL, Kim SW. N-Acetylcysteine, a glutamate modulator, in the treatment of trichotillomania: a double-blind, placebo-controlled study. Arch Gen Psychiatry. 2009;66(7):756–63.PubMedCrossRefGoogle Scholar
  72. 72.
    Berk M, Copolov DL, Dean O, Lu K, Jeavons S, Schapkaitz I, et al. N-Acetyl cysteine for depressive symptoms in bipolar disorder—a double-blind randomized placebo-controlled trial. Biol Psychiatry. 2008;64(6):468–75.PubMedCrossRefGoogle Scholar
  73. 73.
    Berk M, Copolov D, Dean O, Lu K, Jeavons S, Schapkaitz I, et al. N-Acetyl cysteine as a glutathione precursor for schizophrenia—a double-blind, randomized, placebo-controlled trial. Biol Psychiatry. 2008;64(5):361–8.PubMedCrossRefGoogle Scholar
  74. 74.
    Hardan AY, Fung LK, Libove RA, Obukhanych TV, Nair S, Herzenberg LA, et al. A randomized controlled pilot trial of oral N-acetylcysteine in children with autism. Biol Psychiatry. 2012;71(11):956–61.PubMedCrossRefGoogle Scholar
  75. 75.
    RUPP. Risperidone in children with autism and serious behavioral problems. N Engl J Med. 2002;347(5):314–21.CrossRefGoogle Scholar
  76. 76.
    Javitt DC, Schoepp D, Kalivas PW, Volkow ND, Zarate C, Merchant K, et al. Translating glutamate: from pathophysiology to treatment. Sci Transl Med. 2011;3(102):102mr2.PubMedCentralPubMedCrossRefGoogle Scholar
  77. 77.
    Wolff JJ, Gu H, Gerig G, Elison JT, Styner M, Gouttard S, et al. Differences in white matter fiber tract development present from 6 to 24 months in infants with autism. Am J Psychiatry. 2012;169(6):589–600.PubMedCentralPubMedCrossRefGoogle Scholar
  78. 78.
    Rinne JO, Brooks DJ, Rossor MN, Fox NC, Bullock R, Klunk WE, et al. 11C-PiB PET assessment of change in fibrillar amyloid-beta load in patients with Alzheimer’s disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol. 2010;9(4):363–72.PubMedCrossRefGoogle Scholar
  79. 79.
    Nithianantharajah J, Hannan AJ. Enriched environments, experience-dependent plasticity and disorders of the nervous system. Nat Rev Neurosci. 2006;7(9):697–709.PubMedCrossRefGoogle Scholar
  80. 80.
    Restivo L, Ferrari F, Passino E, Sgobio C, Bock J, Oostra BA, et al. Enriched environment promotes behavioral and morphological recovery in a mouse model for the fragile X syndrome. Proc Natl Acad Sci USA. 2005;102(32):11557–62.PubMedCentralPubMedCrossRefGoogle Scholar
  81. 81.
    Pagnamenta AT, Khan H, Walker S, Gerrelli D, Wing K, Bonaglia MC, et al. Rare familial 16q21 microdeletions under a linkage peak implicate cadherin 8 (CDH8) in susceptibility to autism and learning disability. J Med Genet. 2011;48(1):48–54.PubMedCentralPubMedCrossRefGoogle Scholar
  82. 82.
    Wang K, Zhang H, Ma D, Bucan M, Glessner JT, Abrahams BS, et al. Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature. 2009;459(7246):528–33.PubMedCentralPubMedCrossRefGoogle Scholar
  83. 83.
    Sanders SJ, Ercan-Sencicek AG, Hus V, Luo R, Murtha MT, Moreno-De-Luca D, et al. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron. 2011;70(5):863–85.PubMedCentralPubMedCrossRefGoogle Scholar
  84. 84.
    Grau C, Arato K, Fernandez-Fernandez JM, Valderrama A, Sindreu C, Fillat C, et al. DYRK1A-mediated phosphorylation of GluN2A at Ser (1048) regulates the surface expression and channel activity of GluN1/GluN2A receptors. Front Cell Neurosci. 2014;8:331.PubMedCentralPubMedCrossRefGoogle Scholar
  85. 85.
    Betancur C, Sakurai T, Buxbaum JD. The emerging role of synaptic cell-adhesion pathways in the pathogenesis of autism spectrum disorders. Trends Neurosci. 2009;32(7):402–12.PubMedCrossRefGoogle Scholar
  86. 86.
    Ramoz N, Reichert JG, Smith CJ, Silverman JM, Bespalova IN, Davis KL, et al. Linkage and association of the mitochondrial aspartate/glutamate carrier SLC25A12 gene with autism. Am J Psychiatry. 2004;161(4):662–9.PubMedCrossRefGoogle Scholar
  87. 87.
    Gauthier J, Spiegelman D, Piton A, Lafreniere RG, Laurent S, St-Onge J, et al. Novel de novo SHANK3 mutation in autistic patients. Am J Med Genet B Neuropsychiatr Genet. 2009;150B(3):421–4.PubMedCrossRefGoogle Scholar
  88. 88.
    Gauthier J, Champagne N, Lafreniere RG, Xiong L, Spiegelman D, Brustein E, et al. De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia. Proc Natl Acad Sci USA. 2010;107(17):7863–8.PubMedCentralPubMedCrossRefGoogle Scholar
  89. 89.
    Durand CM, Betancur C, Boeckers TM, Bockmann J, Chaste P, Fauchereau F, et al. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet. 2007;39(1):25–7.PubMedCentralPubMedCrossRefGoogle Scholar
  90. 90.
    Berkel S, Marshall CR, Weiss B, Howe J, Roeth R, Moog U, et al. Mutations in the SHANK2 synaptic scaffolding gene in autism spectrum disorder and mental retardation. Nat Genet. 2010;42(6):489–91.PubMedCrossRefGoogle Scholar
  91. 91.
    Sato D, Lionel AC, Leblond CS, Prasad A, Pinto D, Walker S, et al. SHANK1 deletions in males with autism spectrum disorder. Am J Hum Genet. 2012;90(5):879–87.PubMedCentralPubMedCrossRefGoogle Scholar
  92. 92.
    Guilmatre A, Huguet G, Delorme R, Bourgeron T. The emerging role of SHANK genes in neuropsychiatric disorders. Dev Neurobiol. 2014;74(2):113–22.PubMedCrossRefGoogle Scholar
  93. 93.
    Fassio A, Patry L, Congia S, Onofri F, Piton A, Gauthier J, et al. SYN1 loss-of-function mutations in autism and partial epilepsy cause impaired synaptic function. Hum Mol Genet. 2011;20(12):2297–307.PubMedCrossRefGoogle Scholar
  94. 94.
    Corradi A, Fadda M, Piton A, Patry L, Marte A, Rossi P, et al. SYN2 is an autism predisposing gene: loss-of-function mutations alter synaptic vesicle cycling and axon outgrowth. Hum Mol Genet. 2014;23(1):90–103.PubMedCentralPubMedCrossRefGoogle Scholar
  95. 95.
    Weiss LA, Shen Y, Korn JM, Arking DE, Miller DT, Fossdal R, et al. Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med. 2008;358(7):667–75.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  1. 1.Division of Child and Adolescent Psychiatry, Department of Psychiatry and Behavioral SciencesStanford University School of MedicineStanfordUSA

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