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Excitotoxicity in Autism

The Role of Glutamate in Pathogenesis and Treatment

  • Chapter
Autism

Part of the book series: Current Clinical Neurology ((CCNEU))

Abstract

Autism spectrum disorders are neurodevelopmental disorders characterized by deficits in social skills, communication, and motor function, as well as compulsive and repetitive behaviors and interests. Although these disorders are thought to be of multifactorial origin, with a wide range of genetic and environmental factors implicated, we propose that excitoxicity is the mechanism modulating numerous risk factors. Substantial evidence from a number of sources—including laboratory studies, neuroimaging, postmortem data, and genetic studies—supports a role for excitotoxicity in autism spectrum disorders. These studies often implicate glutamate and glutamatergic dysregulation as the key mechanism driving excitotoxic processes. The relationship of autism spectrum disorders to other diseases in which glutamate plays a critical role gives further support to the glutamatergic theory of autism. If glutamate contributes to the pathology of autism spectrum disorders, it is reasonable to suggest that agents modulating glutamate may have some utility in treatment. To this end, numerous reports have supported roles for medications including memantine, depakote, amantadine, and antipsychotics in the treatment of these disorders. Investigations thus far have consisted mainly of small open-label and uncontrolled studies; larger controlled studies are necessary and are underway.

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References

  1. Carlson, NR (2001). Physiology of behavior (7th edn, pp. 96–129). Boston: Allyn and Bacon.

    Google Scholar 

  2. Olney JW. Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate. Science 1969;164(880):719–21.

    Article  PubMed  CAS  Google Scholar 

  3. Bittigau P, Ikonomidou C. Glutamate in neurologic diseases. J Child Neurol 1997;12(8):471–85.

    Article  PubMed  CAS  Google Scholar 

  4. Rubenstein JL, Merzenich MM. Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav 2003;2(5):255–67.

    Article  PubMed  CAS  Google Scholar 

  5. Belmonte MK, Cook EH Jr, Anderson GM, et al. Autism as a disorder of neural information processing: directions for research and targets for therapy. Mol Psychiatry 2004;9(7):646–63.

    PubMed  CAS  Google Scholar 

  6. Polleux F, Lauder JM. Toward a developmental neurobiology of autism. Ment Retard Dev Disabil Res Rev 2004;10(4):303–17.

    Article  PubMed  Google Scholar 

  7. Kornhuber J, Mack-Burkhardt F, Konradi C, Fritze J, Riederer P. Effect of antemortem and postmortem factors on [3H]MK-801 binding in the human brain: transient elevation during early childhood. Life Sci 1989;45(8):745–9.

    Article  PubMed  CAS  Google Scholar 

  8. Shinohe A, Hashimoto K, Nakamura K, et al. Increased serum levels of glutamate in adult patients with autism. Prog Neuropsychopharmacol Biol Psychiatry 2006;30(8):1472–7.

    Article  PubMed  CAS  Google Scholar 

  9. 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.

    Article  PubMed  Google Scholar 

  10. Moreno-Fuenmayor H, Borjas L, Arrieta A, Valera V, Socorro-Candanoza L. Plasma excitatory amino acids in autism. Invest Clin 1996;37(2):113–28.

    PubMed  CAS  Google Scholar 

  11. Rolf LH, Haarmann FY, Grotemeyer KH, Kehrer H. Serotonin and amino acid content in platelets of autistic children. Acta Psychiatr Scand 1993;87(5):312–6.

    Article  PubMed  CAS  Google Scholar 

  12. McGale EH, Pye IF, Stonier C, Hutchinson EC, Aber GM. Studies of the inter-relationship between cerebrospinal fluid and plasma amino acid concentrations in normal individuals. J Neurochem 1977;29(2):291–7.

    Article  PubMed  CAS  Google Scholar 

  13. Alfredsson G, Wiesel FA, Tylec A. Relationships between glutamate and monoamine metabolites in cerebrospinal fluid and serum in healthy volunteers. Biol Psychiatry 1988;23(7):689–97.

    Article  PubMed  CAS  Google Scholar 

  14. Hamberger A, Gillberg C, Palm A, Hagberg B. Elevated CSF glutamate in Rett syndrome. Neuropediatrics 1992;23(4):212–3.

    Article  PubMed  CAS  Google Scholar 

  15. Kurup RK, Kurup PA. A hypothalamic digoxin-mediated model for autism. Int J Neurosci. 2003;113(11):1537–59.

    Article  PubMed  Google Scholar 

  16. Page LA, Daly E, Schmitz N, 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.

    Article  PubMed  Google Scholar 

  17. DeVito TJ, Drost DJ, Neufeld RW, et al. Evidence for cortical dysfunction in autism: a proton magnetic resonance spectroscopic imaging study. Biol Psychiatry 2007;61(4):465–73.

    Article  PubMed  Google Scholar 

  18. Friedman SD, Shaw DW, Artru AA, et al. Regional brain chemical alterations in young children with autism spectrum disorder. Neurology 2003;60(1):100–7.

    PubMed  CAS  Google Scholar 

  19. Fatemi SH, Halt AR, Stary JM, Kanodia R, Schulz SC, Realmuto GR. Glutamic acid decarboxylase 65 and 67 kDa proteins are reduced in autistic parietal and cerebellar cortices. Biol Psychiatry 2002;52(8):805–10.

    Article  PubMed  CAS  Google Scholar 

  20. Yip J, Soghomonian JJ, Blatt GJ. Decreased GAD67 mRNA levels in cerebellar Purkinje cells in autism: pathophysiological implications. Acta Neuropathol (Berl) 2007;113(5):559–68.

    Article  CAS  Google Scholar 

  21. 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.

    PubMed  CAS  Google Scholar 

  22. Blatt GJ, Fitzgerald CM, Guptill JT, Booker AB, Kemper TL, Bauman ML. Density and distribution of hippocampal neurotransmitter receptors in autism: an autoradiographic study. J Autism Dev Disord 2001;31(6):537–43.

    Article  PubMed  CAS  Google Scholar 

  23. Cohly HH, Panja A. Immunological findings in autism. Int Rev Neurobiol 2005;71:317–41.

    Article  PubMed  CAS  Google Scholar 

  24. Licinio J, Alvarado I, Wong ML. Autoimmunity in autism. Mol Psychiatry 2002;7(4):329.

    Article  PubMed  CAS  Google Scholar 

  25. Fatemi SH, Cuadra AE, El-Fakahany EE, Sidwell RW, Thuras P. Prenatal viral infection causes alterations in nNOS expression in developing mouse brains. Neuroreport 2000;11(7):1493–6.

    Article  PubMed  CAS  Google Scholar 

  26. Zimmerman AW, Jyonouchi H, Comi AM, et al. Cerebrospinal fluid and serum markers of inflammation in autism. Pediatr Neurol 2005;33(3):195–201.

    Article  PubMed  Google Scholar 

  27. Chez MG, Burton Q, Dowling T, Chang M, Khanna P, Kramer C. Memantine as adjunctive therapy in children diagnosed with autistic spectrum disorders: An observation of initial clinical response and maintenance tolerability. J Child Neurol 2007 May;22(5):574–9.

    Google Scholar 

  28. Volkmar FR, Pauls D. Autism. Lancet 2003;362(9390):1133–41.

    Article  PubMed  Google Scholar 

  29. Tuchman R. Autism. Neurol Clin 2003;21(4):915–32, viii.

    Article  PubMed  Google Scholar 

  30. Tuchman R, Rapin I. Epilepsy in autism. Lancet Neurol 2002;1(6):352–8.

    Article  PubMed  Google Scholar 

  31. Hussman JP. Suppressed GABAergic inhibition as a common factor in suspected etiologies of autism. J Autism Dev Disord 2001;31(2):247–8.

    Article  PubMed  CAS  Google Scholar 

  32. Anagnostou E, Esposito K, Soorya L, Chaplin W, Wasserman S, Hollander E. Divalproex versus placebo for the prevention of irritability associated with fluoxetine treatment in autism spectrum disorder. J Clin Psychopharmacol 2006;26(4):444–6.

    Article  PubMed  Google Scholar 

  33. Hollander E, Soorya L, Wasserman S, Esposito K, Chaplin W, Anagnostou E. Divalproex sodium vs. placebo in the treatment of repetitive behaviours in autism spectrum disorder. Int J Neuropsychopharmacol 2006;9(2):209–13.

    Article  PubMed  CAS  Google Scholar 

  34. Hollander E, Dolgoff-Kaspar R, Cartwright C, Rawitt R, Novotny S. An open trial of divalproex sodium in autism spectrum disorders. J Clin Psychiatry 2001;62(7):530–4.

    Article  PubMed  CAS  Google Scholar 

  35. Belmonte MK, Bourgeron T. Fragile X syndrome and autism at the intersection of genetic and neural networks. Nat Neurosci 2006;9(10):1221–5.

    Article  PubMed  CAS  Google Scholar 

  36. Veenstra-VanderWeele J, Cook EH Jr. Molecular genetics of autism spectrum disorder. Mol Psychiatry 2004;9(9):819–32.

    Article  PubMed  CAS  Google Scholar 

  37. Wassink TH, Brzustowicz LM, Bartlett CW, Szatmari P. The search for autism disease genes. Ment Retard Dev Disabil Res Rev 2004;10(4):272–83.

    Article  PubMed  Google Scholar 

  38. Autism Genome Project Consortium. Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet 2007;39(3):319–28.

    Article  Google Scholar 

  39. Jamain S, Betancur C, Quach H, et al. Paris Autism Research International Sibpair (PARIS) Study. Linkage and association of the glutamate receptor 6 gene with autism. Mol Psychiatry 2002;7(3):302–10.

    Article  PubMed  CAS  Google Scholar 

  40. Shuang M, Liu J, Jia MX, et al. Family-based association study between autism and glutamate receptor 6 gene in Chinese Han trios. Am J Med Genet B Neuropsychiatr Genet 2004;131(1):48–50.

    Article  Google Scholar 

  41. Jamain S, Betancur C, Quach H, et al. Paris Autism Research International Sibpair (PARIS) Study. Linkage and association of the glutamate receptor 6 gene with autism. Mol Psychiatry 2002;7(3):302–10.

    Article  PubMed  CAS  Google Scholar 

  42. Sutcliffe JS, Nurmi EL, Lombroso PJ. Genetics of childhood disorders: XLVII. Autism, part 6: duplication and inherited susceptibility of chromosome 15q11-q13 genes in autism. J Am Acad Child Adolesc Psychiatry 2003;42(2):253–6.

    Article  PubMed  Google Scholar 

  43. Cook EH Jr, Courchesne RY, Cox NJ, et al. Linkage-disequilibrium mapping of autistic disorder, with 15q11–13 markers. Am J Hum Genet 1998;62(5):1077–83.

    Article  PubMed  CAS  Google Scholar 

  44. Buxbaum JD, Silverman JM, Smith CJ, et al. Association between a GABRB3 polymorphism and autism. Mol Psychiatry 2002;7(3):311–16.

    Article  PubMed  CAS  Google Scholar 

  45. Maestrini E, Lai C, Marlow A, Matthews N, Wallace S, Bailey A, Cook EH, Weeks DE, Monaco AP. Serotonin transporter (5-HTT) and gamma-aminobutyric acid receptor subunit beta3 (GABRB3) gene polymorphisms are not associated with autism in the IMGSA families. The International Molecular Genetic Study of Autism Consortium. Am J Med Genet 1999;88(5):492–6.

    Article  PubMed  CAS  Google Scholar 

  46. Martin ER, Menold MM, Wolpert CM, et al. Analysis of linkage disequilibrium in gamma-aminobutyric acid receptor subunit genes in autistic disorder. Am J Med Genet 2000;96(1):43–8.

    Article  PubMed  Google Scholar 

  47. Menold MM, Shao Y, Wolpert CM, et al. Association analysis of chromosome 15 gabaa receptor subunit genes in autistic disorder. J Neurogenet 2001;15(3–4):245–59.

    Article  PubMed  CAS  Google Scholar 

  48. McCauley JL, Olson LM, Delahanty R, et al. A linkage disequilibrium map of the 1-Mb 15q12 GABA(A) receptor subunit cluster and association to autism. Am J Med Genet B Neuropsychiatr Genet 2004;131(1):51–9.

    Article  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  50. Ramanathan S, Woodroffe A, Flodman PL, et al. 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 2004;5:10.

    Article  PubMed  Google Scholar 

  51. Ramoz N, Reichert JG, Smith CJ, et al. Linkage and association of the mitochondrial aspartate/glutamate carrier SLC25A12 gene with autism. Am J Psychiatry 2004 April;161(4):662–9.

    Google Scholar 

  52. Segurado R, Conroy J, Meally E, Fitzgerald M, Gill M, Gallagher L. Confirmation of association between autism and the mitochondrial aspartate/glutamate carrier SLC25A12 gene on chromosome 2q31. Am J Psychiatry 2005;162(11):2182–4.

    Article  PubMed  Google Scholar 

  53. Blasi F, Bacchelli E, Carone S, Toma C, Monaco AP, Bailey AJ, Maestrini E; International Molecular Genetic Study of Autism Consortium (IMGSAC). SLC25A12 and CMYA3 gene variants are not associated with autism in the IMGSAC multiplex family sample. Eur J Hum Genet 2006;14(1):123–6.

    PubMed  CAS  Google Scholar 

  54. Rabionet R, McCauley JL, Jaworski JM, Ashley-Koch AE, Martin ER, Sutcliffe JS, Haines JL, DeLong GR, Abramson RK, Wright HH, Cuccaro ML, Gilbert JR, Pericak-Vance MA. Lack of association between autism and SLC25A12. Am J Psychiatry 2006;163(5):929–31.

    Article  PubMed  Google Scholar 

  55. Correia C, Coutinho AM, Diogo L, et al. Brief report: High frequency of biochemical markers for mitochondrial dysfunction in autism: no association with the mitochondrial aspartate/glutamate carrier SLC25A12 gene. J Autism Dev Disord 2006;36(8):1137–40.

    Article  PubMed  Google Scholar 

  56. Badner JA, Gershon ES. Regional meta-analysis of published data supports linkage of autism with markers on chromosome 7. Mol Psychiatry 2002;7(1):56–66.

    Article  PubMed  CAS  Google Scholar 

  57. Rabionet R, Jaworski JM, Ashley-Koch AE, et al. Analysis of the autism chromosome 2 linkage region: GAD1 and other candidate genes. Neurosci Lett 2004;372(3):209–14.

    Article  PubMed  CAS  Google Scholar 

  58. McFarlane HG, Kusek GK, Yang M, Phoenix JL, Bolivar VJ, Crawley JN. Autism-like behavioral phenotypes in BTBR T+tf/J mice. Genes Brain Behav. 2007 Jun 7; [Epub ahead of print]

    Google Scholar 

  59. Hagerman RJ, Ono MY, Hagerman PJ. Recent advances in fragile X: A model for autism and neurodegeneration. Curr Opin Psychiatry 2005;18(5):490–6.

    Article  PubMed  Google Scholar 

  60. Muddashetty RS, Kelic S, Gross C, Xu M, Bassell GJ. Dysregulated metabotropic glutamate receptor-dependent translation of AMPA receptor and postsynaptic density-95 mRNAs at synapses in a mouse model of fragile X syndrome. J Neurosci 2007 May 16;27(20):5338–48.

    Google Scholar 

  61. Tucker B, Richards RI, Lardelli M. Contribution of mGluR and Fmr1 functional pathways to neurite morphogenesis, craniofacial development and fragile X syndrome. Hum Mol Genet 2006 Dec 1;15(23):3446–58.

    Google Scholar 

  62. Marui T, Funatogawa I, Koishi S, et al. Tachykinin 1 (TAC1) gene SNPs and haplotypes with autism: A case-control study. Brain Dev 2007 Mar 19; [Epub ahead of print]

    Google Scholar 

  63. Marui T, Koishi S, Funatogawa I, et al. No association between the neuronal pentraxin II gene polymorphism and autism. Prog Neuropsychopharmacol Biol Psychiatry 2007;31(4):940–3.

    Article  PubMed  CAS  Google Scholar 

  64. Barnes CA, Danysz W, Parsons CG. Effects of the uncompetitive NMDA receptor antagonist memantine on hippocampal long-term potentiation, short-term exploratory modulation and spatial memory in awake, freely moving rats. Eur J Neurosci. 1996 Mar;8(3):565–71.

    Google Scholar 

  65. Zajaczkowski W, Quack G, Danysz W. Infusion of (+) -MK-801 and memantine—contrasting effects on radial maze learning in rats with entorhinal cortex lesion. Eur J Pharmacol 1996;296(3):239–46.

    Article  PubMed  CAS  Google Scholar 

  66. Danysz W, Parsons CG, Quack G. NMDA channel blockers: memantine and amino-aklylcyclohexanes—in vivo characterization. Amino Acids 2000;19(1):167–72.

    Article  PubMed  CAS  Google Scholar 

  67. Chez M, Hing P, Chin K, Memon S, Kirschner S. Memantine experience in children and adolescents with autism spectrum disorders. Ann. Neurol. 2004;56:S8.

    Google Scholar 

  68. 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 (Berl). 2007 Mar;191(1):141–7.

    Google Scholar 

  69. King BH, Wright DM, Handen BL, 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.

    Article  PubMed  CAS  Google Scholar 

  70. Uvebrant P, Bauziene R. Intractable epilepsy in children. The efficacy of lamotrigine treatment, including non-seizure-related benefits. Neuropediatrics 1994;25(6):284–9.

    Article  PubMed  CAS  Google Scholar 

  71. Belsito KM, Law PA, Kirk KS, Landa RJ, Zimmerman AW. Lamotrigine therapy for autistic disorder: a randomized, double-blind, placebo-controlled trial. J Autism Dev Disord 2001;31(2):175–81.

    Article  PubMed  CAS  Google Scholar 

  72. 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):2115–17.

    Article  PubMed  Google Scholar 

  73. Woodard C, Groden J, Goodwin M, Shanower C, Bianco J. The treatment of the behavioral sequelae of autism with dextromethorphan: A case report. J Autism Dev Disord 2005;35(4):515–18.

    Article  PubMed  Google Scholar 

  74. Welch L, Sovner R. The treatment of a chronic organic mental disorder with dextromethorphan in a man with severe mental retardation. Br J Psychiatry 1992;161:118–20.

    Article  PubMed  CAS  Google Scholar 

  75. Woodard C, Groden J, Goodwin M, Bodfish J. A placebo double-blind pilot study of dextromethorphan for problematic behaviors in children with autism. Autism 2007;11(1):29–41.

    Article  PubMed  Google Scholar 

  76. Nilsson M, Waters S, Waters N, Carlsson A, Carlsson ML. A behavioural pattern analysis of hypoglutamatergic mice—effects of four different antipsychotic agents. J Neural Transm 2001;108(10):1181–96.

    Article  PubMed  CAS  Google Scholar 

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  1. Psychiatrist at Northern Westchester Hospital in Mt, Kisco, NY

    Martin Evers

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  2. Eric Hollander
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Evers, M., Hollander, E. (2008). Excitotoxicity in Autism. In: Autism. Current Clinical Neurology. Humana Press. https://doi.org/10.1007/978-1-60327-489-0_6

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  • DOI: https://doi.org/10.1007/978-1-60327-489-0_6

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