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

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Abstract

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.

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References

  • 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 82:150–159

    Article  PubMed  CAS  Google Scholar 

  • 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 56:992–1003

    Article  PubMed  CAS  Google Scholar 

  • Atlas D (2001) Functional and physical coupling of voltage-sensitive calcium channels with exocytotic proteins: ramifications for the secretion mechanism, J Neurochem 77:972–985

    Article  PubMed  CAS  Google Scholar 

  • 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 82:165–173

    Article  PubMed  CAS  Google Scholar 

  • Barresi R and Campbell KP (2006) Dystroglycan: from biosynthesis to pathogenesis of human disease, J Cell Sci 119:199–207

    Article  PubMed  CAS  Google Scholar 

  • 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 87:1059–1068

    Article  PubMed  CAS  Google Scholar 

  • Bear MF, Huber KM and Warren ST (2004) The mGluR theory of fragile X mental retardation, Trends Neurosci 27:370–377

    Article  PubMed  CAS  Google Scholar 

  • Biederer T and Südhof TC (2001) CASK and protein 4.1 support F-actin nucleation on neurexins, J Biol Chem 276:47869–47876

    PubMed  CAS  Google Scholar 

  • 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 141:220–221

    Google Scholar 

  • 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 356:581–588

    Article  PubMed  CAS  Google Scholar 

  • Bolliger MF, Pei J, Maxeiner S et al. (2008) Unusually rapid evolution of Neuroligin-4 in mice, Proc Natl Acad Sci USA 105:6421–6426

    Article  PubMed  Google Scholar 

  • 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 48:229–236

    Article  PubMed  CAS  Google Scholar 

  • Budreck EC and Scheiffele P (2007) Neuroligin-3 is a neuronal adhesion protein at GABAergic and glutamatergic synapses, Eur J Neurosci 26:1738–1748

    Article  PubMed  Google Scholar 

  • 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 94:773–782

    Article  PubMed  CAS  Google Scholar 

  • Chen X, Liu H, Shim AH et al. (2008) Structural basis for synaptic adhesion mediated by neuroligin–neurexin interactions, Nat Struct Mol Biol 15:50–56

    Article  PubMed  CAS  Google Scholar 

  • Chih B, Afridi SK, Clark L et al. (2004) Disorder-associated mutations lead to functional inactivation of neuroligins, Hum Mol Genet 13:1471–1477

    Article  PubMed  CAS  Google Scholar 

  • Chih B, Gollan L and Scheiffele P (2006) Alternative splicing controls selective trans-synaptic interactions of the neuroligin–neurexin complex, Neuron 51:171–178

    Article  PubMed  CAS  Google Scholar 

  • Chubykin AA, Atasoy D, Etherton MR et al. (2007) Activity-dependent validation of excitatory versus inhibitory synapses by neuroligin-1 versus neuroligin-2. Neuron 54:919–931

    Article  PubMed  CAS  Google Scholar 

  • 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 280:22365–22374

    Article  PubMed  CAS  Google Scholar 

  • 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 24:4889–4893

    Article  PubMed  CAS  Google Scholar 

  • 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 278:50497–50505

    Article  PubMed  CAS  Google Scholar 

  • Comoletti D, Flynn RE, Boucard AA et al. (2006) Gene selection, alternative splicing, and post-translational processing regulate neuroligin selectivity for beta-neurexins, Biochemistry 45:12816–12827

    Article  PubMed  CAS  Google Scholar 

  • Dean C, Scholl FG, Choih J et al. (2003) Neurexin mediates the assembly of presynaptic terminals, Nat Neurosci 6:708–716

    Article  PubMed  CAS  Google Scholar 

  • 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 39:25–27

    Article  PubMed  CAS  Google Scholar 

  • 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 56:979–991

    Article  PubMed  CAS  Google Scholar 

  • Fu Z, Washbourne P, Ortinski P et al. (2003) Functional excitatory synapses in HEK293 cells expressing neuroligin and glutamate receptors, J Neurophysiol 90:3950–3957

    Article  PubMed  CAS  Google Scholar 

  • Futai K, Kim MJ, Hashikawa T et al. (2007) Retrograde modulation of presynaptic release probability through signaling mediated by PSD-95-neuroligin, Nat Neurosci 10:186–195

    Article  PubMed  CAS  Google Scholar 

  • 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 26:4256–4265

    Article  PubMed  CAS  Google Scholar 

  • Graf ER, Zhang X, Jin SX et al. (2004) Neurexins induce differentiation of GABA and glutamate postsynaptic specializations via neuroligins, Cell 119:1013–1026

    Article  PubMed  CAS  Google Scholar 

  • 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 16:2488–2494

    PubMed  CAS  Google Scholar 

  • 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 28:6055–6067

    Article  PubMed  CAS  Google Scholar 

  • 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 273:21105–21110

    Article  PubMed  CAS  Google Scholar 

  • 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 99:7746–7750

    Article  PubMed  CAS  Google Scholar 

  • 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 28:1697–1708

    Article  PubMed  CAS  Google Scholar 

  • Ichtchenko K, Hata Y, Nguyen T et al. (1995) Neuroligin 1: a splice site-specific ligand for beta-neurexins, Cell 81:435–443

    Article  PubMed  CAS  Google Scholar 

  • Ichtchenko K, Nguyen T and Südhof TC (1996) Structures, alternative splicing, and neurexin binding of multiple neuroligins, J Biol Chem 271:2676–2682

    Article  PubMed  CAS  Google Scholar 

  • Iida J, Hirabayashi S, Sato Y et al. (2004) Synaptic scaffolding molecule is involved in the synaptic clustering of neuroligin, Mol Cell Neurosci 27:497–508

    Article  PubMed  CAS  Google Scholar 

  • Irie M, Hata Y, Takeuchi M et al. (1997) Binding of neuroligins to PSD-95. Science 277:1511–1515

    Article  PubMed  CAS  Google Scholar 

  • 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 34:27–29

    Article  PubMed  CAS  Google Scholar 

  • 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 105:1710–1715

    Article  PubMed  Google Scholar 

  • Kim HG, Kishikawa S, Higgins AW et al. (2008a) Disruption of neurexin 1 associated with autism spectrum disorder, Am J Hum Genet 82:199–207

    Article  PubMed  CAS  Google Scholar 

  • 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 USA

    Google Scholar 

  • 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 105:1873–1878

    Article  PubMed  Google Scholar 

  • Kootz JP, Marinelli B and Cohen DJ (1981) Sensory receptor sensitivity in autistic children: response times to proximal and distal stimulation, Arch Gen Psychiatry 38:271–273

    PubMed  CAS  Google Scholar 

  • 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 74:552–557

    Article  PubMed  CAS  Google Scholar 

  • 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 279:19051–19063

    Article  PubMed  CAS  Google Scholar 

  • 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 25:4898–4907

    Article  PubMed  CAS  Google Scholar 

  • Maximov A, Südhof TC and Bezprozvanny I (1999) Association of neuronal calcium channels with modular adaptor proteins, J Biol Chem 274:24453–24456

    Article  PubMed  CAS  Google Scholar 

  • 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 47:724–733

    Article  PubMed  CAS  Google Scholar 

  • Missler M, Zhang W, Rohlmann A et al. (2003) Alpha-neurexins couple Ca2+ channels to synaptic vesicle exocytosis, Nature 423:939–948

    Article  PubMed  CAS  Google Scholar 

  • 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 26:319–327

    Article  PubMed  CAS  Google Scholar 

  • Mukherjee K, Sharma M, Urlaub H et al. (2008) CASK Functions as a Mg2+-independent neurexin kinase, Cell 133:328–339

    Article  PubMed  CAS  Google Scholar 

  • Nam CI and Chen L (2005) Postsynaptic assembly induced by neurexin-neuroligin interaction and neurotransmitter, Proc Natl Acad Sci USA 102:6137–6142

    Article  PubMed  CAS  Google Scholar 

  • Oertel WH and Mugnaini E (1984) Immunocytochemical studies of GABAergic neurons in rat basal ganglia and their relations to other neuronal systems, Neurosci Lett 47:233–238

    Article  PubMed  CAS  Google Scholar 

  • Petrenko AG, Ullrich B, Missler M et al. (1996) Structure and evolution of neurexophilin, J Neurosci 16:4360–4369

    PubMed  CAS  Google Scholar 

  • 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 112:124–130

    PubMed  Google Scholar 

  • 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 101:13915–13920

    Article  PubMed  CAS  Google Scholar 

  • Rowen L, Young J, Birditt B et al. (2002) Analysis of the human neurexin genes: alternative splicing and the generation of protein diversity, Genomics 79:587–597

    Article  PubMed  CAS  Google Scholar 

  • Rudenko G, Hohenester E and Muller YA (2001) LG/LNS domains: multiple functions – one business end? Trends Biochem Sci 26:363–368

    Article  PubMed  CAS  Google Scholar 

  • 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 99:93–101

    Article  PubMed  CAS  Google Scholar 

  • Sara Y, Biederer T, Atasoy D et al. (2005) Selective capability of SynCAM and neuroligin for functional synapse assembly, J Neurosci 25:260–270

    Article  PubMed  CAS  Google Scholar 

  • Scheiffele P, Fan J, Choih J et al. (2000) Neuroligin expressed in nonneuronal cells triggers presynaptic development in contacting axons, Cell 101:657–669

    Article  PubMed  CAS  Google Scholar 

  • Sebat J, Lakshmi B, Malhotra D et al. (2007) Strong association of de novo copy number mutations with autism, Science 316:445–449

    Article  PubMed  CAS  Google Scholar 

  • 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:e42

    Article  PubMed  CAS  Google Scholar 

  • Shen KC, Kuczynska DA, Wu IJ et al. (2008) Regulation of neurexin 1beta tertiary structure and ligand binding through alternative splicing, Structure 16:422–431

    Article  PubMed  CAS  Google Scholar 

  • Sheng M and Kim E (2000) The Shank family of scaffold proteins, J Cell Sci 113 (Pt 11):1851–1856

    PubMed  CAS  Google Scholar 

  • 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 96:1100–1105

    Article  PubMed  CAS  Google Scholar 

  • Squire LR and Zola SM (1996) Structure and function of declarative and nondeclarative memory systems, Proc Natl Acad Sci USA 93:13515–13522

    Article  PubMed  CAS  Google Scholar 

  • 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 30:405–416

    Article  PubMed  CAS  Google Scholar 

  • Sugita S, Saito F, Tang J et al. (2001) A stoichiometric complex of neurexins and dystroglycan in brain, J Cell Biol 154:435–445

    Article  PubMed  CAS  Google Scholar 

  • Szatmari P, Paterson AD, Zwaigenbaum L et al. (2007) Mapping autism risk loci using genetic linkage and chromosomal rearrangements, Nat Genet 39:319–328

    Article  PubMed  CAS  Google Scholar 

  • Tabuchi K, Blundell J, Etherton MR et al. (2007) A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice, Science 318:71–76

    Article  PubMed  CAS  Google Scholar 

  • Tabuchi K and Südhof TC (2002) Structure and evolution of neurexin genes: insight into the mechanism of alternative splicing, Genomics 79:849–859

    Article  PubMed  CAS  Google Scholar 

  • 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 14:497–507

    Article  PubMed  CAS  Google Scholar 

  • Ushkaryov YA, Petrenko AG, Geppert M et al. (1992) Neurexins: synaptic cell surface proteins related to the alpha-latrotoxin receptor and laminin, Science 257:50–56

    Article  PubMed  CAS  Google Scholar 

  • Varoqueaux F, Aramuni G, Rawson RL et al. (2006) Neuroligins determine synapse maturation and function, Neuron 51:741–754

    Article  PubMed  CAS  Google Scholar 

  • Varoqueaux F, Jamain S and Brose N (2004) Neuroligin 2 is exclusively localized to inhibitory synapses, Eur J Cell Biol 83:449–456

    Article  PubMed  CAS  Google Scholar 

  • Zhao X, Leotta A, Kustanovich V et al. (2007) A unified genetic theory for sporadic and inherited autism, Proc Natl Acad Sci USA 104:12831–12836

    Article  PubMed  CAS  Google Scholar 

  • Zoghbi HY (2003) Postnatal neurodevelopmental disorders: meeting at the synapse? Science 302:826–830

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

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

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  1. The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, 77 Massachusetts Avenue, 46-3301, Cambridge, MA 02139, USA

    Alexander A. Chubykin

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Correspondence to Alexander A. Chubykin .

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    Chubykin, A.A. (2009). Neurexins and Neuroligins: A Synaptic Code for Neuronal Wiring That Is Implicated in Autism. In: Umemori, H., Hortsch, M. (eds) The Sticky Synapse. Springer, New York, NY. https://doi.org/10.1007/978-0-387-92708-4_17

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