Advertisement

Synaptic Abnormalities and Candidate Genes in Autism

  • Ridha Joober
  • Alaa El-Husseini

1. Summary

Autism is one of the most genetically determined neuropsychiatric disorders. The risk for first-degree relatives is approximately 100-fold higher than the risk in the general population and the concordance in monozygotic (MZ) twins (60–90%) is much higher than the concordance in dizygotic (DZ) twins (∼3%). Although specific genes implicated in autism have not been firmly identified, mutations in two members of the neuroligin family of cell adhesion molecules have been reported. Recent findings suggest that alterations in neuroligin function may result in an imbalance in excitatory to inhibitory synaptic transmission. These findings are consistent with a recent model for autism which proposes that enhanced neuronal excitability is the leading cause for autism. In this chapter we briefly discuss the difficulties encountered in identifying genes implicated in autism. We propose that advances in understanding the biological mechanism of synapse development will help to overcome these difficulties.

Keywords

Autistic Patient Inhibitory Synaptic Transmission DIDATE Genes Neuroligin Family 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

9. References

  1. 1.
    Kanner, L. (1943) Nervous Child 2, 217–250.Google Scholar
  2. 2.
    Fombonne, E. (2002) Mol Psychiatry 7Suppl 2, S4–S6.PubMedCrossRefGoogle Scholar
  3. 3.
    American Psychiatric Association: (1994) Diagnostic and Statistical Manual of Mental Diseases, Fourth Edition. American Psychiatric Association., Washington, DC.Google Scholar
  4. 4.
    Rutter, M., Silberg, J., O’Connor, T., and Simonoff, E. (1999) J Child Psychol Psychiatry 40, 19–55.PubMedCrossRefGoogle Scholar
  5. 5.
    Bailey, A., Le Couteur, A., Gottesman, I., Bolton, P., Simonoff, E., Yuzda, E., and Rutter, M. (1995) Psychol Med 25, 63–77.PubMedCrossRefGoogle Scholar
  6. 6.
    Le Couteur, A., Bailey, A., Goode, S., Pickles, A., Robertson, S., Gottesman, I., and Rutter, M. (1996) J Child Psychol Psychiatry Allied Disciplines 37, 785–801.CrossRefGoogle Scholar
  7. 7.
    Ritvo, E.R., Freeman, B.J., Mason-Brothers, A., Mo, A., and Ritvo, A.M. (1985) Am J Psychiatry 142, 74–77.PubMedGoogle Scholar
  8. 8.
    Steffenburg, S., Gillberg, C., Hellgren, L., Andersson, L., Gillberg, I.C., Jakobsson, G., and Bohman, M. (1989) J Child Psychol Psychiatry 30, 405–416.PubMedCrossRefGoogle Scholar
  9. 9.
    Szatmari, P., Jones, M.B., Zwaigenbaum, L., and MacLean, J.E. (1998) J Autism Dev Disord 28, 351–368.PubMedCrossRefGoogle Scholar
  10. 10.
    Pickles, A., Bolton, P., Macdonald, H., Bailey, A., Le Couteur, A., Sim, C.H., and Rutter, M. (1995) A J Hum Genet 57, 717–726.Google Scholar
  11. 11.
    Gillberg, C. (1998) J Autism Dev Disord 28, 415–425.PubMedCrossRefGoogle Scholar
  12. 12.
    Lauritsen, M., Mors, O., Mortensen, P.B., and Ewald, H. (1999) J Child Psychol Psychiatry 40, 335–345.PubMedCrossRefGoogle Scholar
  13. 13.
    Schroer, R.J., Phelan, M.C., Michaelis, R.C., Crawford, E.C., Skinner, S.A., Cuccaro, M., Simensen, R.J., Bishop, J., Skinner, C., Fender, D., and Stevenson, R.E. (1998) Am J Med Genet 76, 327–336.PubMedCrossRefGoogle Scholar
  14. 14.
    Bailey, A., Luthert, P., Bolton, P., Le Couteur, A., Rutter, M., and Harding, B. (1993) Lancet 341, 1225–1226.PubMedCrossRefGoogle Scholar
  15. 15.
    Fombonne, E., Roge, B., Claverie, J., Courty, S., and Fremolle, J. (1999) J Autism Dev Disord 29, 113–119.PubMedCrossRefGoogle Scholar
  16. 16.
    Reik, W. (1996) Exp Physiol 81, 161–172.PubMedGoogle Scholar
  17. 17.
    International Molecular Genetic Study of Autism Consortium (1998) Hum Mol Genet 7, 571–578.CrossRefGoogle Scholar
  18. 18.
    Barrett, S., Beck, J.C., Bernier, R., Bisson, E., Braun, T.A., Casavant, T.L., Childress, D., Folstein, S.E., Garcia, M., Gardiner, M.B., Gilman, S., Haines, J.L., Hopkins, K., Landa, R., Meyer, N.H., Mullane, J.A., Nishimura, D.Y., Palmer, P., Piven, J., Purdy, J., Santangelo, S.L., Searby, C., Sheffield, V., Singleton, J., and Slager, S. (1999) Am J Med Genet 88, 609–615.PubMedCrossRefGoogle Scholar
  19. 19.
    Philippe, A., Martinez, M., Guilloud-Bataille, M., Gillberg, C., Rastam, M., Sponheim, E., Coleman, M., Zappella, M., Aschauer, H., van Malldergerme, L., Penet, C., Feingold, J., Brice, A., and Leboyer, M. (1999) Hum Mol Genet 8, 805–812.PubMedCrossRefGoogle Scholar
  20. 20.
    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., Petersen, P.B., Pingree, C., McMahon, W., Wong, D.L., Cavalli-Sforza, L.L., Kraemer, H.C., and Myers, R.M. (1999) Am J Hum Genet 65, 493–507.PubMedCrossRefGoogle Scholar
  21. 21.
    Liu, J., Nyholt, D.R., Magnussen, P., Parano, E., Pavone, P., Geschwind, D., Lord, C., Iversen, P., Hoh, J., Ott, J., and Gilliam, T.C. (2001) Am J Hum Genet 2001 69, 327–340.CrossRefGoogle Scholar
  22. 22.
    Shao, Y., Wolpert, C.M., Raiford, K.L., Menold, M.M., Donnelly, S.L., Ravan, S.A., Bass, M.P., McClain, C., von Wendt, L., Vance, J.M., Abramson, R.H., Wright, H.H., Ashley-Koch, A., Gilbert, J.R., DeLong, R.G., Cuccaro, M.L., and Pericak-Vance, M.A. (2002) Am J Med Genet 114, 99–105.PubMedCrossRefGoogle Scholar
  23. 23.
    Shao, Y., Raiford, K.L., Wolpert, C.M., Cope, H.A., Ravan, S.A., Ashley-Koch, A.A., Abramson, R.K., Wright, H.H., DeLong, R.G., Gilbert, J.R., Cuccaro, M.L., and Pericak-Vance, M.A. (2002) Am J Hum Genet 70, 1058–1061.PubMedCrossRefGoogle Scholar
  24. 24.
    Alarcon, M., Cantor, R.M., Liu, J., Gilliam, T.C., and Geschwind, D.H. (2002) Am J Hum Genet 70, 60–71.PubMedCrossRefGoogle Scholar
  25. 25.
    Petit, E., Herault, J., Martineau, J., Perrot, A., Barthelemy, C., Hameury, L., Sauvage, D., Lelord, G., and Muh, J.P. (1995) J Med Genet 32, 269–274.PubMedCrossRefGoogle Scholar
  26. 26.
    Herault, J., Martineau, J., Petit, E., Perrot, A., Sauvage, D., Barthelemy, C., Mallet, J., Muh, J.P., and Lelord, G. (1994) J Autism Dev Disord 24, 233–236.PubMedCrossRefGoogle Scholar
  27. 27.
    Cook, E.H., Jr., Courchesne, R., Lord, C., Cox, N.J., Yan, S., Lincoln, A., Haas, R., Courchesne, E., and Leventhal, B.L. (1997) Mol Psychiatry 2, 247–250.PubMedCrossRefGoogle Scholar
  28. 28.
    Yirmiya, N., Pilowsky, T., Nemanov, L., Arbelle, S., Feinsilver, T., Fried, I., and Ebstein, R.P. (2001) Am J Med Genet 105, 381–386.PubMedCrossRefGoogle Scholar
  29. 29.
    Klauck, S.M., Poustka, F., Benner, A., Lesch, K.P., and Poustka, A. (1997) Hum Mol Genet 6, 2233–2238.PubMedCrossRefGoogle Scholar
  30. 30.
    Tordjman, S., Gutknecht, L., Carlier, M., Spitz, E., Antoine, C., Slama, F., Carsalade, V., Cohen, D.J., Ferrari, P., Roubertoux, P.L., and Anderson, G.M. (2001) Mol Psychiatry 6, 434–439.PubMedCrossRefGoogle Scholar
  31. 31.
    Persico, A.M., Militerni, R., Bravaccio, C., Schneider, C., Melmed, R., Conciatori, M., Damiani, V., Baldi, A., and Keller, F. (2000) Am J Med Genet 96, 123–127.PubMedCrossRefGoogle Scholar
  32. 32.
    Betancur, C., Corbex, M., Spielewoy, C., Philippe, A., Laplanche, J.L., Launay, J.M., Gillberg, C., Mouren-Simeoni, M.C., Hamon, M., Giros, B., Nosten-Bertrand, M., and Leboyer, M. (2002) Mol Psychiatry 7, 67–71.PubMedCrossRefGoogle Scholar
  33. 33.
    Cook, E.H., Jr., Courchesne, R.Y., Cox, N.J., Lord, C., Gonen, D., Guter, S.J., Lincoln, A., Nix, K., Haas, R., Leventhal, B.L., and Courchesne, E. (1998) Am J Hum Genet 62, 1077–1083.PubMedCrossRefGoogle Scholar
  34. 34.
    Buxbaum, J.D., Silverman, J.M., Smith, C.J., Greenberg, D.A., Kilifarski, M., Reichert, J., Cook, E.H., Jr., Fang, Y., Song, C.Y., and Vitale, R. (2002) Mol Psychiatry 7, 311–316.PubMedCrossRefGoogle Scholar
  35. 35.
    Martin, E.R., Menold, M.M., Wolpert, C.M., Bass, M.P., Donnelly, S.L., Ravan, S.A., Zimmerman, A., Gilbert, J.R., Vance, J.M., Maddox, L.O., Wright, H.H., Abramson, R.K., DeLong, G.R., Cuccaro, M.L., and Pericak-Vance, M.A. (2000) Am J Med Genet 96, 43–48.PubMedCrossRefGoogle Scholar
  36. 36.
    Menold, M.M., Shao, Y., Wolpert, C.M., Donnelly, S.L., Raiford, K.L., Martin, E.R., Ravan, S.A., Abramson, R.K., Wright, H.H., DeLong, G.R., Cuccaro, M.L., Pericak-Vance, M.A., and Gilbert, J.R. (2001) J Neurogenet 15, 245–259.PubMedCrossRefGoogle Scholar
  37. 37.
    Salmon, B., Hallmayer, J., Rogers, T., Kalaydjieva, L., Petersen, P.B., Nicholas, P., Pingree, C., McMahon, W., Spiker, D., Lotspeich, L., Kraemer, H., McCague, P., Dimiceli, S., Nouri, N., Pitts, T., Yang, J., Hinds, D., Myers, R.M., and Risch, N. (1999) Am J Med Genet 88, 551–556.PubMedCrossRefGoogle Scholar
  38. 38.
    Risch, N. (1990) Am J Hum Genet 46, 222–228.PubMedGoogle Scholar
  39. 39.
    Frankel, W.N., and Schork, N.J. (1996) Nat Genet 14, 371–373.PubMedCrossRefGoogle Scholar
  40. 40.
    Zoghbi, H.Y. (2003) Science 302, 826–830.PubMedCrossRefGoogle Scholar
  41. 41.
    Vanderklish, P.W., and Edelman, G.M. (2005) Genes Brain Behav 4, 360–384.PubMedCrossRefGoogle Scholar
  42. 42.
    Jamain, S., Quach, H., Betancur, C., Rastam, M., Colineaux, C., Gillberg, I.C., Soderstrom, H., Giros, B., Leboyer, M., Gillberg, C., and Bourgeron, T. (2003) Nat Genet 34, 27–29.PubMedCrossRefGoogle Scholar
  43. 43.
    Laumonnier, F., Bonnet-Brilhault, F., Gomot, M., Blanc, R., David, A., Moizard, M.P., Raynaud, M., Ronce, N., Lemonnier, E., Calvas, P., Laudier, B., Chelly, J., Fryns, J.P., Ropers, H.H., Hamel, B.C., Andres, C., Barthelemy, C., Moraine, C., and Briault, S. (2004) Am J Hum Genet 74, 552–557.PubMedCrossRefGoogle Scholar
  44. 44.
    Gauthier, J., Bonnel, A., St-Onge, J., Karemera, L., Laurent, S., Mottron, L., Fombonne, E., Joober, R., and Rouleau, G.A. (2005) Am J Med Genet B Neuropsychiatr Genet 132, 74–75.PubMedGoogle Scholar
  45. 45.
    Vincent, J.B., Kolozsvari, D., Roberts, W.S., Bolton, P.F., Gurling, H.M., and Scherer, S.W. (2004) Am J Med Genet B Neuropsychiatr Genet 129, 82–84.PubMedCrossRefGoogle Scholar
  46. 46.
    Rubenstein, J.L., and Merzenich, M.M. (2003) Genes Brain Behav 2, 255–267.PubMedCrossRefGoogle Scholar
  47. 47.
    Zhang, L.I., Bao, S., and Merzenich, M.M. (2002) Proc Natl Acad Sci U S A 99, 2309–2314.PubMedCrossRefGoogle Scholar
  48. 48.
    Zhang, L.I., Bao, S., and Merzenich, M.M. (2001) Nat Neurosci 4, 1123–1130.PubMedCrossRefGoogle Scholar
  49. 49.
    Ferster, D. (2004) Science 303, 1619–1621.PubMedCrossRefGoogle Scholar
  50. 50.
    Hensch, T.K., Fagiolini, M., Mataga, N., Stryker, M.P., Baekkeskov, S., and Kash, S.F. (1998) Science 282, 1504–1508.PubMedCrossRefGoogle Scholar
  51. 51.
    Shumyatsky, G.P., Tsvetkov, E., Malleret, G., Vronskaya, S., Hatton, M., Hampton, L., Battey, J.F., Dulac, C., Kandel, E.R., and Bolshakov, V.Y. (2002) Cell 111, 905–918.PubMedCrossRefGoogle Scholar
  52. 52.
    Levitt, P. (2005) Epilepsia 46Suppl 7:22–28.PubMedCrossRefGoogle Scholar
  53. 53.
    Sporns, O., Tononi, G., and Edelman, G.M. (2000) Cereb Cortex 10, 127–141.PubMedCrossRefGoogle Scholar
  54. 54.
    Beckel-Mitchener, A., and Greenough, W.T. (2004) Ment Retard Dev Disabil Res Rev 10, 53–59.PubMedCrossRefGoogle Scholar
  55. 55.
    Raymond, G.V., Bauman, M.L., and Kemper, T.L. (1996) Acta Neuropathol 91, 117–119.PubMedCrossRefGoogle Scholar
  56. 56.
    Williams, R.S., Hauser, S.L., Purpura, D.P., Delong, G.R., and Swisher, C.N. (1980) Arch Neurol 37, 749–753.PubMedGoogle Scholar
  57. 57.
    Casanova, M.F., Buxhoeveden, D.P., Switala, A.E., and Roy, E. (2002) Neurology 58, 428–432.PubMedGoogle Scholar
  58. 58.
    Bailey, A., Luthert, P., Dean, A., Harding, B., Janota, I., Montgomery, M., Rutter, M., and Lantos, P. (1998) Brain 121, 889–905.PubMedCrossRefGoogle Scholar
  59. 59.
    Courchesne, E., Carper, R., and Akshoomoff, N. (2003) J Am Ment Assoc 290, 337–344.CrossRefGoogle Scholar
  60. 60.
    Carper, R.A., Moses, P., Tigue, Z.D., and Courchesne, E. (2002) Neuroimage 16, 1038–1051.PubMedCrossRefGoogle Scholar
  61. 61.
    Waites, C.L., Craig, A.M., and Garner, C.C. (2005) Annu Rev Neurosci 28, 251–274.PubMedCrossRefGoogle Scholar
  62. 62.
    Levinson, J.N., and El-Husseini, A. (2005) Neuron 48, 171–174.PubMedCrossRefGoogle Scholar
  63. 63.
    Kim, E., and Sheng, M. (2004) Nat Rev Neurosci 5, 771–781.PubMedCrossRefGoogle Scholar
  64. 64.
    Rao, A., Kim, E., Sheng, M., and Craig, A.M. (1998) J Neurosci 18, 1217–1229.PubMedGoogle Scholar
  65. 65.
    Scheiffele, P. (2003) Annu Rev Neurosci 26, 485–508.PubMedCrossRefGoogle Scholar
  66. 66.
    El-Husseini, A.E., Schnell, E., Chetkovich, D.M., Nicoll, R.A., and Bredt, D.S. (2000) Science 290, 1364–1368.PubMedGoogle Scholar
  67. 67.
    Prange, O., Wong, T.P., Gerrow, K., Wang, Y.T., and El-Husseini, A. (2004) Proc Natl Acad Sci U S A 101, 13915–13920.PubMedCrossRefGoogle Scholar
  68. 68.
    Huang, K., and El-Husseini, A. (2005) Curr Opin Neurobiol 15, 527–535.PubMedCrossRefGoogle Scholar
  69. 69.
    Bao, J., Lin, H., Ouyang, Y., Lei, D., Osman, A., Kim, T.W., Mei, L., Dai, P., Ohlemiller, K.K., and Ambron, R.T. (2004) Nat Neurosci 7, 1250–1258.PubMedCrossRefGoogle Scholar
  70. 70.
    Yao, W.D., Gainetdinov, R.R., Arbuckle, M.I., Sotnikova, T.D., Cyr, M., Beaulieu, J.M., Torres, G.E., Grant, S.G., and Caron, M.G. (2004) Neuron 41, 625–638.PubMedCrossRefGoogle Scholar
  71. 71.
    Todd, P.K., Mack, K.J., and Malter, J.S. (2003) Proc Natl Acad Sci U S A 100, 14374–14378.PubMedCrossRefGoogle Scholar
  72. 72.
    Auranen, M., Varilo, T., Alen, R., Vanhala, R., Ayers, K., Kempas, E., Ylisaukko-Oja, T., Peltonen, L., and Jarvela, I. (2003) Mol Psychiatry 8, 879–884.PubMedCrossRefGoogle Scholar
  73. 73.
    Oliveira, G., Matoso, E., Vicente, A., Ribeiro, P., Marques, C., Ataide, A., Miguel, T., Saraiva, J., and Carreira, I. (2003) J Autism Dev Disord 33, 177–185.PubMedCrossRefGoogle Scholar
  74. 74.
    Auranen, M., Vanhala, R., Varilo, T., Ayers, K., Kempas, E., Ylisaukko-Oja, T., Sinsheimer, J.S., Peltonen, L., and Jarvela, I. (2002) Am J Hum Genet 71, 777–790.PubMedCrossRefGoogle Scholar
  75. 75.
    Konstantareas, M.M., and Homatidis, S. (1999) J Autism Dev Disord 29, 275–285.PubMedCrossRefGoogle Scholar
  76. 76.
    Mariner, R., Jackson, A.W., III, Levitas, A., Hagerman, R.J., Braden, M., McBogg, P.M., Smith, A.C., and Berry, R. (1986) J Autism Dev Disord 16, 425–440.PubMedCrossRefGoogle Scholar
  77. 77.
    Yonan, A.L., Alarcon, M., Cheng, R., Magnusson, P.K., Spence, S.J., Palmer, A.A., Grunn, A., Juo, S.H., Terwilliger, J.D., Liu, J., Cantor, R.M., Geschwind, D.H., and Gilliam, T.C. (2003) Am J Hum Genet 73, 886–897.PubMedCrossRefGoogle Scholar
  78. 78.
    Nagase, T., Ishikawa, K., Suyama, M., Kikuno, R., Hirosawa, M., Miyajima, N., Tanaka, A., Kotani, H., Nomura, N., and Ohara, O. (1999) DNA Res 6, 63–70.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2006

Authors and Affiliations

  • Ridha Joober
    • 1
  • Alaa El-Husseini
    • 2
  1. 1.Departments of Psychiatry, Neurology and Human GeneticsMcGill UniversityMontrealCanada
  2. 2.Department of Psychiarty and the Brain Research CentreUniversity of British ColumbiaVancouverCanada

Personalised recommendations