Cell Adhesion Molecules in Synaptopathies

  • Thomas BourgeronEmail author


Synaptopathies are human disorders caused by a defect in synapse formation or function. In the first 3 years of life, the ability of children for learning is impressive and correlates with an intense phase of synaptogenesis in their brains. During this critical period, cell adhesion molecules (CAMs) are crucial factors for the identification of the appropriate partner cell and the formation of a functional synapse. Consistent with their key roles in brain development, mutations in brain CAMs can lead to a variety of neurological disorders such as deafness, epilepsy, mental retardation, and autism spectrum conditions (ASC). Furthermore, polymorphisms of brain CAMs within the human population may also play a role in the susceptibility to milder cognitive disorders. This chapter reports several examples of CAM mutations that are associated with human brain disorders and highlights the emerging key roles of these molecules in the susceptibility to neurologic and psychiatric conditions.


Autism Psychiatry Synapse Synaptogenesis 



I would like to thank Michael Hortsch and Hisashi Umemori for their critical reading of this chapter. This work was supported by the Pasteur Institute, INSERM, Assistance Publique-Hôpitaux de Paris, FP6 TISM MOLGEN, FP6 ENI-NET, Fondation Orange, Fondation de France, Fondation biomédicale de la Mairie de Paris, Fondation pour la Recherche Médicale and FondaMental.


  1. Abrahams BS, Tentler D, Perederiy JV et al. (2007) Genome-wide analyses of human perisylvian cerebral cortical patterning. Proc Natl Acad Sci USA 104:17849–17854CrossRefPubMedGoogle Scholar
  2. Alarcon M, Abrahams BS, Stone JL et al. (2008) Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. Am J Hum Genet 82:150–159CrossRefPubMedGoogle Scholar
  3. Arking DE, Cutler DJ, Brune CW et al. (2008) A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism. Am J Hum Genet 82:160–164CrossRefPubMedGoogle Scholar
  4. Bakkaloglu B, O’oak BJ, Louvi A et al. (2008) Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders. Am J Hum Genet 82:165–173CrossRefPubMedGoogle Scholar
  5. Belloso JM, Bache I, Guitart M et al. (2007) Disruption of the CNTNAP2 gene in a t(7;15) translocation family without symptoms of Gilles de la Tourette syndrome. Eur J Hum Genet 15:711–713CrossRefPubMedGoogle Scholar
  6. Blasi F, Bacchelli E, Pesaresi G et al. (2006) Absence of coding mutations in the X-linked genes neuroligin 3 and neuroligin 4 in individuals with autism from the IMGSAC collection. Am J Med Genet B Neuropsychiatr Genet 141:220–221Google Scholar
  7. Boeckers TM, Bockmann J, Kreutz MR et al. (2002) ProSAP/Shank proteins – a family of higher order organizing molecules of the postsynaptic density with an emerging role in human neurological disease. J Neurochem 81:903–910CrossRefPubMedGoogle Scholar
  8. Bonora E, Lamb JA, Barnby G et al. (2005) Mutation screening and association analysis of six candidate genes for autism on chromosome 7q. Eur J Hum Genet 13:198–207CrossRefPubMedGoogle Scholar
  9. Boyle ME, Berglund EO, Murai KK et al. (2001) Contactin orchestrates assembly of the septate-like junctions at the paranode in myelinated peripheral nerve. Neuron 30:385–397CrossRefPubMedGoogle Scholar
  10. Bray NJ, Kirov G, Owen RJ et al. (2002) Screening the human protocadherin 8 (PCDH8) gene in schizophrenia. Genes Brain Behav 1:187–191CrossRefPubMedGoogle Scholar
  11. Chih B, Afridi SK, Clark L et al. (2004) Disorder-associated mutations lead to functional inactivation of neuroligins. Hum Mol Genet 13:1471–1477CrossRefPubMedGoogle Scholar
  12. Chih B, Gollan L and Scheiffele P (2006) Alternative splicing controls selective trans-synaptic interactions of the neuroligin-neurexin complex. Neuron 51:171–178CrossRefPubMedGoogle Scholar
  13. Chocholska S, Rossier E, Barbi G et al. (2006) Molecular cytogenetic analysis of a familial interstitial deletion Xp22.2–22.3 with a highly variable phenotype in female carriers. Am J Med Genet A 140:604–610PubMedGoogle Scholar
  14. Chubykin AA, Atasoy D, Etherton MR et al. (2007) Activity-Dependent Validation of Excitatory versus Inhibitory Synapses by Neuroligin-1 versus Neuroligin-2. Neuron 54:919–931CrossRefPubMedGoogle Scholar
  15. Comoletti D, De Jaco A, Jennings LL et al. (2004) The Arg451Cys-neuroligin-3 mutation associated with autism reveals a defect in protein processing. J Neurosci 24:4889–4893CrossRefPubMedGoogle Scholar
  16. Comoletti D, Flynn RE, Boucard AA et al. (2006) Gene selection, alternative splicing, and post-translational processing regulate neuroligin selectivity for beta-neurexins. Biochemistry 45:12816–12827CrossRefPubMedGoogle Scholar
  17. Craig AM and Kang Y (2007) Neurexin-neuroligin signaling in synapse development. Curr Opin Neurobiol 17:43–52CrossRefPubMedGoogle Scholar
  18. Dalva MB, McClelland AC and Kayser MS (2007) Cell adhesion molecules: signalling functions at the synapse. Nature Rev 8:206–220Google Scholar
  19. Daoud H, Bonnet-Brilhault F, Védrine S et al. (2008) NLGN4X Gene overexpression is associated with autism and profound mental retardation. Poster at the International Meeting for Autism Research (IMFAR), London, 2008Google Scholar
  20. Denaxa M, Kyriakopoulou K, Theodorakis K et al. (2005) The adhesion molecule TAG-1 is required for proper migration of the superficial migratory stream in the medulla but not of cortical interneurons. Dev Biol 288:87–99CrossRefPubMedGoogle Scholar
  21. Dibbens LM, Tarpey PS, Hynes K et al. (2008) X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment. Nature Genet 40:776–781CrossRefPubMedGoogle Scholar
  22. Durand CM, Betancur C, Boeckers TM et al. (2007) Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nature Genet 39:25–27CrossRefPubMedGoogle Scholar
  23. Durand CM and Bourgeron T (2008) Genetic, neurobiological and clinical findings related to SHANK3 mutations and 22q13 chromosomal rearrangements in autism spectrum disorders. Eur J Psychiatry 1:58–61Google Scholar
  24. Durand CM, Kappeler C, Betancur C et al. (2006) Expression and genetic variability of PCDH11Y, a gene specific to Homo sapiens and candidate for susceptibility to psychiatric disorders. Am J Med Genet B Neuropsychiatr Genet 141:67–70Google Scholar
  25. Esumi S, Kakazu N, Taguchi Y et al. (2005) Monoallelic yet combinatorial expression of variable exons of the protocadherin-alpha gene cluster in single neurons. Nature Genet 37:171–176CrossRefPubMedGoogle Scholar
  26. Fernandez T, Morgan T, Davis N et al. (2004) Disruption of contactin 4 (CNTN4) results in developmental delay and other features of 3p deletion syndrome. Am J Hum Genet 74:1286–1293CrossRefPubMedGoogle Scholar
  27. Fernandez T, Morgan T, Davis N et al. (2008) Disruption of Contactin 4 (CNTN4) results in developmental delay and other features of 3p deletion syndrome. Am J Hum Genet 82:1385CrossRefPubMedGoogle Scholar
  28. Frazer KA, Ballinger DG, Cox DR et al. (2007) A second generation human haplotype map of over 3.1 million SNPs. Nature 449:851–861CrossRefPubMedGoogle Scholar
  29. Freitag CM (2007) The genetics of autistic disorders and its clinical relevance: a review of the literature. Mol Psychiatry 12:2–22CrossRefPubMedGoogle Scholar
  30. Friedman JI, Vrijenhoek T, Markx S et al. (2008) CNTNAP2 gene dosage variation is associated with schizophrenia and epilepsy. Mol Psychiatry 13:261–266CrossRefPubMedGoogle Scholar
  31. Friedman JM, Baross A, Delaney AD et al. (2006) Oligonucleotide microarray analysis of genomic imbalance in children with mental retardation. Am J Hum Genet 79:500–513CrossRefPubMedGoogle Scholar
  32. Gauthier J, Bonnel A, St-Onge J et al. (2005) NLGN3/NLGN4 gene mutations are not responsible for autism in the Quebec population. Am J Med Genet B Neuropsychiatr Genet 132:74–75Google Scholar
  33. Gauthier J, Spiegelman D, Piton A et al. (2008) Novel de novo SHANK3 mutation in autistic patients. Am J Med Genet B Neuropsychiatr Genet 150B(3):421–424Google Scholar
  34. Graf ER, Zhang X, Jin SX et al. (2004) Neurexins induce differentiation of GABA and glutamate postsynaptic specializations via neuroligins. Cell 119:1013–1026CrossRefPubMedGoogle Scholar
  35. Hilschmann N, Barnikol HU, Barnikol-Watanabe S et al. (2001) The immunoglobulin-like genetic predetermination of the brain: the protocadherins, blueprint of the neuronal network. Die Naturwissenschaften 88:2–12CrossRefPubMedGoogle Scholar
  36. Hines RM, Wu L, Hines DJ et al. (2008) Synaptic imbalance, stereotypies, and impaired social interactions in mice with altered neuroligin 2 expression. J Neurosci 28:6055–6067CrossRefPubMedGoogle Scholar
  37. Hirayama T and Yagi T (2006) The role and expression of the protocadherin-alpha clusters in the CNS. Curr Opin Neurobiol 16:336–342CrossRefPubMedGoogle Scholar
  38. Hishimoto A, Liu QR, Drgon T et al. (2007) Neurexin 3 polymorphisms are associated with alcohol dependence and altered expression of specific isoforms. Hum Mol Genet 16:2880–2891CrossRefPubMedGoogle Scholar
  39. Hung AY, Futai K, Sala C et al. (2008) Smaller dendritic spines, weaker synaptic transmission, but enhanced spatial learning in mice lacking Shank1. J Neurosci 28:1697–1708CrossRefPubMedGoogle Scholar
  40. Hutcheson HB, Olson LM, Bradford Y et al. (2004) Examination of NRCAM, LRRN3, KIAA0716, and LAMB1 as autism candidate genes. BMC Med Genet 5:12CrossRefPubMedGoogle Scholar
  41. Huttenlocher PR and Dabholkar AS (1997) Regional differences in synaptogenesis in human cerebral cortex. J Comp Neurol 387:167–178CrossRefPubMedGoogle Scholar
  42. Jamain S, Quach H, Betancur C et al. (2003) Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nature Genet 34:27–29CrossRefPubMedGoogle Scholar
  43. Jamain S, Radyushkin K, Hammerschmidt K et al. (2008a) Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism. Proc Natl Acad Sci USA 105:1710–1715Google Scholar
  44. Jamain S, Radyushkin K, Hammerschmidt K et al. (2008b) Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism. Proc Natl Acad Sci USA 105:1710–1715CrossRefPubMedGoogle Scholar
  45. Kaneko-Goto T, Yoshihara S, Miyazaki H et al. (2008) BIG-2 mediates olfactory axon convergence to target glomeruli. Neuron 57:834–846CrossRefPubMedGoogle Scholar
  46. Kazmierczak P, Sakaguchi H, Tokita J et al. (2007) Cadherin 23 and protocadherin 15 interact to form tip-link filaments in sensory hair cells. Nature 449:87–91CrossRefPubMedGoogle Scholar
  47. Kent L, Emerton J, Bhadravathi V et al. (2008) X linked ichthyosis (steroid sulphatase deficiency) is associated with increased risk of attention deficit hyperactivity disorder, autism and social communication deficits. J Med Genet 45:519–524CrossRefPubMedGoogle Scholar
  48. Kim HG, Kishikawa S, Higgins AW et al. (2008) Disruption of neurexin 1 associated with autism spectrum disorder. Am J Hum Genet 82:199–207CrossRefPubMedGoogle Scholar
  49. Kirov G, Gumus D, Chen W et al. (2008) Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia. Hum Mol Genet 17:458–465CrossRefPubMedGoogle Scholar
  50. Laumonnier F, Bonnet-Brilhault F, Gomot M et al. (2004) 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 74:552–557CrossRefPubMedGoogle Scholar
  51. Lawson-Yuen A, Saldivar JS, Sommer S et al. (2008) Familial deletion within NLGN4 associated with autism and Tourette syndrome. Eur J Hum Genet 16:614–618CrossRefPubMedGoogle Scholar
  52. Li CY, Liu QR, Zhang PW et al. (2008) OKCAM: an ontology-based, human-centered knowledgebase for cell adhesion molecules. Nucleic Acids Res 37 (Database issue) :D251–60Google Scholar
  53. Li H, Takeda Y, Niki H et al. (2003) Aberrant responses to acoustic stimuli in mice deficient for neural recognition molecule NB-2. Euro J Neurosci 17:929–936CrossRefGoogle Scholar
  54. Macarov M, Zeigler M, Newman JP et al. (2007) Deletions of VCX-A and NLGN4: a variable phenotype including normal intellect. J Intellect Disabil Res 51:329–333CrossRefPubMedGoogle Scholar
  55. Manning MA, Cassidy SB, Clericuzio C et al. (2004) Terminal 22q deletion syndrome: a newly recognized cause of speech and language disability in the autism spectrum. Pediatrics 114:451–457CrossRefPubMedGoogle Scholar
  56. Mattson MP and van Praag H (2008) TAGing APP constrains neurogenesis. Nature Cell Biol 10:249–250CrossRefPubMedGoogle Scholar
  57. Meyer G, Varoqueaux F, Neeb A et al. (2004) The complexity of PDZ domain-mediated interactions at glutamatergic synapses: a case study on neuroligin. Neuropharmacology 47:724–733CrossRefPubMedGoogle Scholar
  58. Moessner R, Marshall CR, Sutcliffe JS et al. (2007) Contribution of SHANK3 mutations to autism spectrum disorder. Am J Hum Genet 81:1289–1297CrossRefPubMedGoogle Scholar
  59. Morrow EM, Yoo SY, Flavell SW et al. (2008) Identifying autism loci and genes by tracing recent shared ancestry. Science (New York, NY) 321:218–223Google Scholar
  60. Nussbaum J, Xu Q, Payne TJ et al. (2008) Significant association of the neurexin-1 gene (NRXN1) with nicotine dependence in European- and African-American smokers. Hum Mol Genet 17:1569–1577CrossRefPubMedGoogle Scholar
  61. Poliak S, Salomon D, Elhanany H et al. (2003) Juxtaparanodal clustering of Shaker-like K+ channels in myelinated axons depends on Caspr2 and TAG-1. J Cell Biol 162:1149–1160CrossRefPubMedGoogle Scholar
  62. Prange O, Wong TP, Gerrow K et al. (2004) A balance between excitatory and inhibitory synapses is controlled by PSD-95 and neuroligin. Proc Natl Acad Sci USA 101:13915–13920CrossRefPubMedGoogle Scholar
  63. Redon R, Ishikawa S, Fitch KR et al. (2006) Global variation in copy number in the human genome. Nature 444:444–454CrossRefPubMedGoogle Scholar
  64. Roohi J, Montagna C, Tegay DH et al. (2008) Disruption of Contactin 4 in 3 Subjects with Autism Spectrum Disorder. J Med Genet 46:176–182CrossRefPubMedGoogle Scholar
  65. Roussignol G, Ango F, Romorini S et al. (2005) Shank expression is sufficient to induce functional dendritic spine synapses in aspiny neurons. J Neurosci 25:3560–3570CrossRefPubMedGoogle Scholar
  66. Roux AF, Faugere V, Le Guedard S et al. (2006) Survey of the frequency of USH1 gene mutations in a cohort of Usher patients shows the importance of cadherin 23 and protocadherin 15 genes and establishes a detection rate of above 90%. J Med Genet 43:763–768CrossRefPubMedGoogle Scholar
  67. Sakurai T, Ramoz N, Reichert JG et al. (2006) Association analysis of the NrCAM gene in autism and in subsets of families with severe obsessive-compulsive or self-stimulatory behaviors. Psychiatric Genet 16:251–257CrossRefGoogle Scholar
  68. Scheiffele P, Fan J, Choih J et al. (2000) Neuroligin expressed in nonneuronal cells triggers presynaptic development in contacting axons. Cell 101:657–669CrossRefPubMedGoogle Scholar
  69. Sebat J, Lakshmi B, Malhotra D et al. (2007) Strong association of de novo copy number mutations with autism. Science (New York, NY) 316:445–449Google Scholar
  70. Shapiro L, Love J and Colman DR (2007) Adhesion molecules in the nervous system: structural insights into function and diversity. Ann Rev Neurosci 30:451–474CrossRefPubMedGoogle Scholar
  71. Strauss KA, Puffenberger EG, Huentelman MJ et al. (2006) Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2. N Engl J Med 354:1370–1377CrossRefPubMedGoogle Scholar
  72. Szatmari P, Paterson AD, Zwaigenbaum L et al. (2007) Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nature Genet 39:319–328CrossRefPubMedGoogle Scholar
  73. Tabuchi K, Blundell J, Etherton MR et al. (2007) A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science (New York, NY) 318:71–76Google Scholar
  74. Tabuchi K and Südhof TC (2002) Structure and evolution of neurexin genes: insight into the mechanism of alternative splicing. Genomics 79:849–859CrossRefPubMedGoogle Scholar
  75. Takeda Y, Akasaka K, Lee S et al. (2003) Impaired motor coordination in mice lacking neural recognition molecule NB-3 of the contactin/F3 subgroup. J Neurobiol 56:252–265CrossRefPubMedGoogle Scholar
  76. Talebizadeh Z, Lam DY, Theodoro MF et al. (2006) Novel splice isoforms for NLGN3 and NLGN4 with possible implications in autism. J Med Genet 43:e21CrossRefPubMedGoogle Scholar
  77. Traka M, Goutebroze L, Denisenko N et al. (2003) Association of TAG-1 with Caspr2 is essential for the molecular organization of juxtaparanodal regions of myelinated fibers. J Cell Biol 162:1161–1172CrossRefPubMedGoogle Scholar
  78. Varoqueaux F, Aramuni G, Rawson RL et al. (2006) Neuroligins determine synapse maturation and function. Neuron 51:741–754CrossRefPubMedGoogle Scholar
  79. Verkerk AJ, Mathews CA, Joosse M et al. (2003) CNTNAP2 is disrupted in a family with Gilles de la Tourette syndrome and obsessive compulsive disorder. Genomics 82:1–9CrossRefPubMedGoogle Scholar
  80. Vincent JB, Kolozsvari D, Roberts WS et al. (2004) Mutation screening of X-chromosomal neuroligin genes: no mutations in 196 autism probands. Am J Med Genet B Neuropsychiatr Genet 129B:82–84CrossRefPubMedGoogle Scholar
  81. Yan J, Feng J, Schroer R et al. (2008a) Analysis of the neuroligin 4Y gene in patients with autism. Psychiatric Genet 18:204–207CrossRefGoogle Scholar
  82. Yan J, Noltner K, Feng J et al. (2008b) Neurexin 1alpha structural variants associated with autism. Neurosci Lett 438:368–370CrossRefPubMedGoogle Scholar
  83. Yan J, Oliveira G, Coutinho A et al. (2004) Analysis of the neuroligin 3 and 4 genes in autism and other neuropsychiatric patients. Mol Psychiatry 10:329–332CrossRefGoogle Scholar
  84. Ylisaukko-oja T, Rehnstrom K, Auranen M et al. (2005) Analysis of four neuroligin genes as candidates for autism. Eur J Hum Genet 13:1285–1292CrossRefPubMedGoogle Scholar
  85. Yoshihara Y, Kawasaki M, Tamada A et al. (1995) Overlapping and differential expression of BIG-2, BIG-1, TAG-1, and F3: four members of an axon-associated cell adhesion molecule subgroup of the immunoglobulin superfamily. J Neurobiol 28:51–69CrossRefPubMedGoogle Scholar
  86. Zahir FR, Baross A, Delaney AD et al. (2008) A patient with vertebral, cognitive and behavioural abnormalities and a de novo deletion of NRXN1alpha. J Med Genet 45:239–243CrossRefPubMedGoogle Scholar
  87. Zheng QY, Yan D, Ouyang XM et al. (2005) Digenic inheritance of deafness caused by mutations in genes encoding cadherin 23 and protocadherin 15 in mice and humans. Hum Mol Genet 14:103–111CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Human Genetics and Cognitive Functions Units, Institut Pasteur, 25 rue du Docteur RouxParisFrance

Personalised recommendations