Neurexins and Neuroligins: A Synaptic Code for Neuronal Wiring That Is Implicated in Autism

  • Alexander A. ChubykinEmail author


Neurexins and neuroligins are neuronal cell adhesion molecules (CAMs), which are specifically expressed in the nervous system and particularly in the brain. Presynaptic neurexins interact with postsynaptic neuroligins in a Ca2+-dependent manner and form trans-synaptic adhesion complexes, which are implicated in synaptogenesis. Differential splicing of neurexin and neuroligin transcripts results in a large variety of isoforms. These isoforms differ in their binding affinities and ligand specificities and are differentially distributed in the central nervous system. This may reflect a synaptic code, which along with other neuronal adhesion molecules determines the wiring diagram of neuronal connections in the brain. Mouse genetic studies suggest that neurexins and neuroligins are involved in the stabilization of transient, rather than the formation of de novo synapses. Mutations in neurexin and neuroligin genes, as well as their downstream signaling molecules, have been identified in patients with mental retardation and autism spectrum disorders. Mice with corresponding mouse mutations represent new promising experimental models, which display the typical phenotypes associated with these diseases. The first results obtained from these models suggest that a disruption of the balance between excitatory and inhibitory neurotransmission (E/I) is one of the potential pathophysiological mechanisms for autism and mental retardation.


Neurexin Neuroligin Synapse formation Synapse stabilization Autism 



The author thanks Thomas C. Südhof and Dilja Krueger for their helpful comments on the manuscript.


  1. 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
  2. Arac D, Boucard AA, Ozkan E et al. (2007) Structures of neuroligin-1 and the neuroligin-1/neurexin-1 beta complex reveal specific protein-protein and protein-Ca2+ interactions, Neuron 56:992–1003CrossRefPubMedGoogle Scholar
  3. Atlas D (2001) Functional and physical coupling of voltage-sensitive calcium channels with exocytotic proteins: ramifications for the secretion mechanism, J Neurochem 77:972–985CrossRefPubMedGoogle Scholar
  4. Bakkaloglu B, O’Roak 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. Barresi R and Campbell KP (2006) Dystroglycan: from biosynthesis to pathogenesis of human disease, J Cell Sci 119:199–207CrossRefPubMedGoogle Scholar
  6. Baumgartner S, Littleton JT, Broadie K et al. (1996) A Drosophila neurexin is required for septate junction and blood-nerve barrier formation and function, Cell 87:1059–1068CrossRefPubMedGoogle Scholar
  7. Bear MF, Huber KM and Warren ST (2004) The mGluR theory of fragile X mental retardation, Trends Neurosci 27:370–377CrossRefPubMedGoogle Scholar
  8. Biederer T and Südhof TC (2001) CASK and protein 4.1 support F-actin nucleation on neurexins, J Biol Chem 276:47869–47876PubMedGoogle Scholar
  9. 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
  10. Bolliger MF, Frei K, Winterhalter KH et al. (2001) Identification of a novel neuroligin in humans which binds to PSD-95 and has a widespread expression, Biochem J 356:581–588CrossRefPubMedGoogle Scholar
  11. Bolliger MF, Pei J, Maxeiner S et al. (2008) Unusually rapid evolution of Neuroligin-4 in mice, Proc Natl Acad Sci USA 105:6421–6426CrossRefPubMedGoogle Scholar
  12. Boucard AA, Chubykin AA, Comoletti D et al. (2005) A splice code for trans-synaptic cell adhesion mediated by binding of neuroligin 1 to alpha- and beta-neurexins, Neuron 48:229–236CrossRefPubMedGoogle Scholar
  13. Budreck EC and Scheiffele P (2007) Neuroligin-3 is a neuronal adhesion protein at GABAergic and glutamatergic synapses, Eur J Neurosci 26:1738–1748CrossRefPubMedGoogle Scholar
  14. Butz S, Okamoto M and Südhof TC (1998) A tripartite protein complex with the potential to couple synaptic vesicle exocytosis to cell adhesion in brain, Cell 94:773–782CrossRefPubMedGoogle Scholar
  15. Chen X, Liu H, Shim AH et al. (2008) Structural basis for synaptic adhesion mediated by neuroligin–neurexin interactions, Nat Struct Mol Biol 15:50–56CrossRefPubMedGoogle Scholar
  16. 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
  17. 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
  18. 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
  19. Chubykin AA, Liu X, Comoletti D et al. (2005) Dissection of synapse induction by neuroligins: effect of a neuroligin mutation associated with autism, J Biol Chem 280:22365–22374CrossRefPubMedGoogle Scholar
  20. 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
  21. Comoletti D, Flynn R, Jennings LL et al. (2003) Characterization of the interaction of a recombinant soluble neuroligin-1 with neurexin-1beta, J Biol Chem 278:50497–50505CrossRefPubMedGoogle Scholar
  22. 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
  23. Dean C, Scholl FG, Choih J et al. (2003) Neurexin mediates the assembly of presynaptic terminals, Nat Neurosci 6:708–716CrossRefPubMedGoogle Scholar
  24. 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, Nat Genet 39:25–27CrossRefPubMedGoogle Scholar
  25. Fabrichny IP, Leone P, Sulzenbacher G et al. (2007) Structural analysis of the synaptic protein neuroligin and its beta-neurexin complex: determinants for folding and cell adhesion, Neuron 56:979–991CrossRefPubMedGoogle Scholar
  26. Fu Z, Washbourne P, Ortinski P et al. (2003) Functional excitatory synapses in HEK293 cells expressing neuroligin and glutamate receptors, J Neurophysiol 90:3950–3957CrossRefPubMedGoogle Scholar
  27. Futai K, Kim MJ, Hashikawa T et al. (2007) Retrograde modulation of presynaptic release probability through signaling mediated by PSD-95-neuroligin, Nat Neurosci 10:186–195CrossRefPubMedGoogle Scholar
  28. Graf ER, Kang Y, Hauner AM et al. (2006) Structure function and splice site analysis of the synaptogenic activity of the neurexin-1 beta LNS domain, J Neurosci 26:4256–4265CrossRefPubMedGoogle Scholar
  29. 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
  30. Hata Y, Butz S and Südhof TC (1996) CASK: a novel dlg/PSD95 homolog with an N-terminal calmodulin-dependent protein kinase domain identified by interaction with neurexins, J Neurosci 16:2488–2494PubMedGoogle Scholar
  31. 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
  32. Hirao K, Hata Y, Ide N et al. (1998) A novel multiple PDZ domain-containing molecule interacting with N-methyl-D-aspartate receptors and neuronal cell adhesion proteins, J Biol Chem 273:21105–21110CrossRefPubMedGoogle Scholar
  33. Huber KM, Gallagher SM, Warren ST et al. (2002) Altered synaptic plasticity in a mouse model of fragile X mental retardation, Proc Natl Acad Sci USA 99:7746–7750CrossRefPubMedGoogle Scholar
  34. 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
  35. Ichtchenko K, Hata Y, Nguyen T et al. (1995) Neuroligin 1: a splice site-specific ligand for beta-neurexins, Cell 81:435–443CrossRefPubMedGoogle Scholar
  36. Ichtchenko K, Nguyen T and Südhof TC (1996) Structures, alternative splicing, and neurexin binding of multiple neuroligins, J Biol Chem 271:2676–2682CrossRefPubMedGoogle Scholar
  37. Iida J, Hirabayashi S, Sato Y et al. (2004) Synaptic scaffolding molecule is involved in the synaptic clustering of neuroligin, Mol Cell Neurosci 27:497–508CrossRefPubMedGoogle Scholar
  38. Irie M, Hata Y, Takeuchi M et al. (1997) Binding of neuroligins to PSD-95. Science 277:1511–1515CrossRefPubMedGoogle Scholar
  39. Jamain S, Quach H, Betancur C et al. (2003) Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism, Nat Genet 34:27–29CrossRefPubMedGoogle Scholar
  40. Jamain S, Radyushkin K, Hammerschmidt K et al. (2008) Reduced social interaction and ultrasonic communication in a mouse model of monogenic heritable autism, Proc Natl Acad Sci USA 105:1710–1715CrossRefPubMedGoogle Scholar
  41. Kim HG, Kishikawa S, Higgins AW et al. (2008a) Disruption of neurexin 1 associated with autism spectrum disorder, Am J Hum Genet 82:199–207CrossRefPubMedGoogle Scholar
  42. Kim J, Jung SY, Lee YK et al. (2008b) Neuroligin-1 is required for normal expression of LTP and associative fear memory in the amygdala of adult animals, Proc Natl Acad Sci USAGoogle Scholar
  43. Koehnke J, Jin X, Budreck EC et al. (2008) Crystal structure of the extracellular cholinesterase-like domain from neuroligin-2. Proc Natl Acad Sci USA 105:1873–1878CrossRefPubMedGoogle Scholar
  44. Kootz JP, Marinelli B and Cohen DJ (1981) Sensory receptor sensitivity in autistic children: response times to proximal and distal stimulation, Arch Gen Psychiatry 38:271–273PubMedGoogle Scholar
  45. 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
  46. Leonoudakis D, Conti LR, Radeke CM et al. (2004) A multiprotein trafficking complex composed of SAP97, CASK, Veli, and Mint1 is associated with inward rectifier Kir2 potassium channels, J Biol Chem 279:19051–19063CrossRefPubMedGoogle Scholar
  47. Marble DD, Hegle AP, Snyder ED, 2nd et al. (2005) Camguk/CASK enhances Ether-a-go-go potassium current by a phosphorylation-dependent mechanism, J Neurosci 25:4898–4907CrossRefPubMedGoogle Scholar
  48. Maximov A, Südhof TC and Bezprozvanny I (1999) Association of neuronal calcium channels with modular adaptor proteins, J Biol Chem 274:24453–24456CrossRefPubMedGoogle Scholar
  49. 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
  50. Missler M, Zhang W, Rohlmann A et al. (2003) Alpha-neurexins couple Ca2+ channels to synaptic vesicle exocytosis, Nature 423:939–948CrossRefPubMedGoogle Scholar
  51. Moretti P, Levenson JM, Battaglia F et al. (2006) Learning and memory and synaptic plasticity are impaired in a mouse model of Rett syndrome, J Neurosci 26:319–327CrossRefPubMedGoogle Scholar
  52. Mukherjee K, Sharma M, Urlaub H et al. (2008) CASK Functions as a Mg2+-independent neurexin kinase, Cell 133:328–339CrossRefPubMedGoogle Scholar
  53. Nam CI and Chen L (2005) Postsynaptic assembly induced by neurexin-neuroligin interaction and neurotransmitter, Proc Natl Acad Sci USA 102:6137–6142CrossRefPubMedGoogle Scholar
  54. Oertel WH and Mugnaini E (1984) Immunocytochemical studies of GABAergic neurons in rat basal ganglia and their relations to other neuronal systems, Neurosci Lett 47:233–238CrossRefPubMedGoogle Scholar
  55. Petrenko AG, Ullrich B, Missler M et al. (1996) Structure and evolution of neurexophilin, J Neurosci 16:4360–4369PubMedGoogle Scholar
  56. Piluso G, Carella M, D’Avanzo M et al. (2003) Genetic heterogeneity of FG syndrome: a fourth locus (FGS4) maps to Xp11.4-p11.3 in an Italian family, Hum Genet 112:124–130PubMedGoogle Scholar
  57. 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
  58. Rowen L, Young J, Birditt B et al. (2002) Analysis of the human neurexin genes: alternative splicing and the generation of protein diversity, Genomics 79:587–597CrossRefPubMedGoogle Scholar
  59. Rudenko G, Hohenester E and Muller YA (2001) LG/LNS domains: multiple functions – one business end? Trends Biochem Sci 26:363–368CrossRefPubMedGoogle Scholar
  60. Rudenko G, Nguyen T, Chelliah Y et al. (1999) The structure of the ligand-binding domain of neurexin Ibeta: regulation of LNS domain function by alternative splicing, Cell 99:93–101CrossRefPubMedGoogle Scholar
  61. Sara Y, Biederer T, Atasoy D et al. (2005) Selective capability of SynCAM and neuroligin for functional synapse assembly, J Neurosci 25:260–270CrossRefPubMedGoogle Scholar
  62. 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
  63. Sebat J, Lakshmi B, Malhotra D et al. (2007) Strong association of de novo copy number mutations with autism, Science 316:445–449CrossRefPubMedGoogle Scholar
  64. Serajee FJ, Zhong H, Nabi R et al. (2003) The metabotropic glutamate receptor 8 gene at 7q31: partial duplication and possible association with autism, J Med Genet 40:e42CrossRefPubMedGoogle Scholar
  65. Shen KC, Kuczynska DA, Wu IJ et al. (2008) Regulation of neurexin 1beta tertiary structure and ligand binding through alternative splicing, Structure 16:422–431CrossRefPubMedGoogle Scholar
  66. Sheng M and Kim E (2000) The Shank family of scaffold proteins, J Cell Sci 113 (Pt 11):1851–1856PubMedGoogle Scholar
  67. Song JY, Ichtchenko K, Südhof TC et al. (1999) Neuroligin 1 is a postsynaptic cell-adhesion molecule of excitatory synapses, Proc Natl Acad Sci USA 96:1100–1105CrossRefPubMedGoogle Scholar
  68. Squire LR and Zola SM (1996) Structure and function of declarative and nondeclarative memory systems, Proc Natl Acad Sci USA 93:13515–13522CrossRefPubMedGoogle Scholar
  69. Steffenburg S, Gillberg C, Hellgren L et al. (1989) A twin study of autism in Denmark, Finland, Iceland, Norway and Sweden, J Child Psychol Psychiatry 30:405–416CrossRefPubMedGoogle Scholar
  70. Sugita S, Saito F, Tang J et al. (2001) A stoichiometric complex of neurexins and dystroglycan in brain, J Cell Biol 154:435–445CrossRefPubMedGoogle Scholar
  71. Szatmari P, Paterson AD, Zwaigenbaum L et al. (2007) Mapping autism risk loci using genetic linkage and chromosomal rearrangements, Nat Genet 39:319–328CrossRefPubMedGoogle Scholar
  72. Tabuchi K, Blundell J, Etherton MR et al. (2007) A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice, Science 318:71–76CrossRefPubMedGoogle Scholar
  73. Tabuchi K and Südhof TC (2002) Structure and evolution of neurexin genes: insight into the mechanism of alternative splicing, Genomics 79:849–859CrossRefPubMedGoogle Scholar
  74. Ullrich B, Ushkaryov YA and Südhof TC (1995) Cartography of neurexins: more than 1000 isoforms generated by alternative splicing and expressed in distinct subsets of neurons, Neuron 14:497–507CrossRefPubMedGoogle Scholar
  75. Ushkaryov YA, Petrenko AG, Geppert M et al. (1992) Neurexins: synaptic cell surface proteins related to the alpha-latrotoxin receptor and laminin, Science 257:50–56CrossRefPubMedGoogle Scholar
  76. Varoqueaux F, Aramuni G, Rawson RL et al. (2006) Neuroligins determine synapse maturation and function, Neuron 51:741–754CrossRefPubMedGoogle Scholar
  77. Varoqueaux F, Jamain S and Brose N (2004) Neuroligin 2 is exclusively localized to inhibitory synapses, Eur J Cell Biol 83:449–456CrossRefPubMedGoogle Scholar
  78. Zhao X, Leotta A, Kustanovich V et al. (2007) A unified genetic theory for sporadic and inherited autism, Proc Natl Acad Sci USA 104:12831–12836CrossRefPubMedGoogle Scholar
  79. Zoghbi HY (2003) Postnatal neurodevelopmental disorders: meeting at the synapse? Science 302:826–830CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.The Picower Institute for Learning and Memory, Massachusetts Institute of TechnologyCambridgeUSA

Personalised recommendations