Advertisement

Neuroligins and Neurexins: Synaptic Bridges Implicated in Autism

  • Craig M. Powell
  • Antony A. Boucard

Abstract

Neuroligins and neurexins are molecules that bridge the gaps between one neuron and another at synapses in the brains of humans and other animals. Recent human clinical genetics studies have revealed mutations in the genes that code for neuroligins and neurexins in some patients with autism spectrum disorders. These mutations alter the function of these synaptic bridge molecules and thereby alter the function of synapses. This leads to abnormally altered communication between neurons in neuronal circuits of the brain. When these mutations in the human genes are reproduced in mice, the mice show abnormal social behaviors and other behaviors relevant to human autism. Using these genetic animal models, neuroscientists are now in a position to decipher the precise functional abnormalities in the brain that result from these autism-associated genetic mutations. Ongoing studies are using recordings from brain slices in these mouse models to understand the exact problems with brain function and to identify drugs or other treatments that can be used to normalize the function of brain synapses and circuits. Efforts to use this information to treat behavioral abnormalities in mouse models and ultimately in patients with autism are underway.

Keywords

Autism Spectrum Disorder Probe Trial Asperger Syndrome Inhibitory Synapse Alternative Splice Site 
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.

References

  1. Arac, D, Boucard, AA, Ozkan, E, Strop, P, Newell, E, Sudhof, TC and Brunger, AT (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.CrossRefPubMedGoogle Scholar
  2. Berninghausen, O, Rahman, MA, Silva, JP, Davletov, B, Hopkins, C and Ushkaryov, YA (2007) Neurexin Ibeta and neuroligin are localized on opposite membranes in mature central synapses. J Neurochem 103: 1855–1863.CrossRefPubMedGoogle Scholar
  3. Biederer, T and Sudhof, TC (2000) Mints as adaptors. Direct binding to neurexins and recruitment of munc18. J Biol Chem 275: 39803–39806.CrossRefPubMedGoogle Scholar
  4. Bolliger, MF, Frei, K, Winterhalter, KH and Gloor, SM (2001) Identification of a novel neuroligin in humans which binds to PSD-95 and has a widespread expression. Biochem J 356: 581–588.CrossRefPubMedGoogle Scholar
  5. Bolliger, MF, Pei, J, Maxeiner, S, Boucard, AA, Grishin, NV and Sudhof, TC (2008) Unusually rapid evolution of Neuroligin-4 in mice. Proc Natl Acad Sci USA 105: 6421–6426.CrossRefPubMedGoogle Scholar
  6. Bonaglia, MC, Giorda, R, Borgatti, R, Felisari, G, Gagliardi, C, Selicorni, A and Zuffardi, O (2001) Disruption of the ProSAP2 gene in a t(12;22)(q24.1;q13.3) is associated with the 22q13.3 deletion syndrome. Am J Hum Genet 69: 261–268.CrossRefPubMedGoogle Scholar
  7. Boucard, AA, Chubykin, AA, Comoletti, D, Taylor, P and Sudhof, TC (2005) A splice-code for trans-synaptic cell adhesion mediated by binding of neuroligin 1 to α- and β-neurexins. Neuron 48(2):229–236.CrossRefPubMedGoogle Scholar
  8. Budreck, EC and Scheiffele, P (2007) Neuroligin-3 is a neuronal adhesion protein at GABAergic and glutamatergic synapses. Eur J Neurosci 26: 1738–1748.CrossRefPubMedGoogle Scholar
  9. Butz, S, Okamoto, M and Sudhof, TC (1998) A tripartite protein complex with the potential to couple synaptic vesicle exocytosis to cell adhesion in brain. Cell 94: 773–782.CrossRefPubMedGoogle Scholar
  10. Chahrour, M and Zoghbi, HY (2007) The story of Rett syndrome: from clinic to neurobiology. Neuron 56: 422–437.CrossRefPubMedGoogle Scholar
  11. Chen, C, Kano, M, Abeliovich, A, Chen, L, Bao, S, Kim, JJ, Hashimoto, K, Thompson, RF and Tonegawa, S (1995) Impaired motor coordination correlates with persistent multiple climbing fiber innervation in PKC gamma mutant mice. Cell 83: 1233–1242.CrossRefPubMedGoogle Scholar
  12. Chen, X, Liu, H, Shim, AH, Focia, PJ and He, X (2008) Structural basis for synaptic adhesion mediated by neuroligin-neurexin interactions. Nat Struct Mol Biol 15: 50–56.CrossRefPubMedGoogle Scholar
  13. Chih, B, Afridi, SK, Clark, L and Scheiffele, P (2004) Disorder-associated mutations lead to functional inactivation of neuroligins. Hum Mol Genet 13: 1471–1477.CrossRefPubMedGoogle Scholar
  14. Chih, B, Engelman, H and Scheiffele, P (2005) Control of excitatory and inhibitory synapse formation by neuroligins. Science 307: 1324–1328.CrossRefPubMedGoogle Scholar
  15. Chubykin, AA, Atasoy, D, Etherton, MR, Brose, N, Kavalali, ET, Gibson, JR and Sudhof, TC (2007) Activity-dependent validation of excitatory versus inhibitory synapses by neuroligin-1 versus neuroligin-2. Neuron 54: 919–931.CrossRefPubMedGoogle Scholar
  16. Chubykin, AA, Liu, X, Comoletti, D, Tsigelny, I, Taylor, P and Sudhof, TC (2005) Dissection of synapse induction by neuroligins: effect of a neuroligin mutation associated with autism. J Biol Chem 280: 22365–22374.CrossRefPubMedGoogle Scholar
  17. Comoletti, D, De Jaco, A, Jennings, LL, Flynn, RE, Gaietta, G, Tsigelny, I, Ellisman, MH and Taylor, P (2004) The Arg451Cys-neuroligin-3 mutation associated with autism reveals a defect in protein processing. J Neurosci 24: 4889–4893.CrossRefPubMedGoogle Scholar
  18. Comoletti, D, Flynn, RE, Boucard, AA, Demeler, B, Schirf, V, Shi, J, Jennings, LL, Newlin, HR, Sudhof, TC and Taylor, P (2006) Gene selection, alternative splicing, and post-translational processing regulate neuroligin selectivity for beta-neurexins. Biochemistry 45: 12816–12827.CrossRefPubMedGoogle Scholar
  19. Dean, C, Scholl, FG, Choih, J, DeMaria, S, Berger, J, Isacoff, E and Scheiffele, P (2003) Neurexin mediates the assembly of presynaptic terminals. Nat Neurosci 6: 708–716.CrossRefPubMedGoogle Scholar
  20. Dresbach, T, Neeb, A, Meyer, G, Gundelfinger, ED and Brose, N (2004) Synaptic targeting of neuroligin is independent of neurexin and SAP90/PSD95 binding. Mol Cell Neurosci 27: 227–235.PubMedGoogle Scholar
  21. Durand, CM, Betancur, C, Boeckers, TM, Bockmann, J, Chaste, P, Fauchereau, F, Nygren, G, Rastam, M, Gillberg, IC, Anckarsater, H, et al. (2007) Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat Genet 39: 25–27.CrossRefPubMedGoogle Scholar
  22. Fabrichny, IP, Leone, P, Sulzenbacher, G, Comoletti, D, Miller, MT, Taylor, P, Bourne, Y and Marchot, P (2007) Structural analysis of the synaptic protein neuroligin and its beta-neurexin complex: determinants for folding and cell adhesion. Neuron 56: 979–991.CrossRefPubMedGoogle Scholar
  23. Feng, J, Schroer, R, Yan, J, Song, W, Yang, C, Bockholt, A, Cook, EH, Skinner, C, Schwartz, CE, Sonner, SS (2006) Neuroscience Letters, 409(1):10–13. Epub 2006 Oct. 16.Google Scholar
  24. Folstein, SE and Rosen-Sheidley, B (2001) Genetics of autism: complex aetiology for a heterogeneous disorder. Nat Rev Genet 2: 943–955.CrossRefPubMedGoogle Scholar
  25. Garber, KB, Visootsak, J and Warren, ST (2008) Fragile X syndrome. Eur J Hum Genet 16: 666–672.CrossRefPubMedGoogle Scholar
  26. Gauthier, J, Bonnel, A, St-Onge, J, Karemera, L, Laurent, S, Mottron, L, Fombonne, E, Joober, R and Rouleau, GA (2005) NLGN3/NLGN4 gene mutations are not responsible for autism in the Quebec population. Am J Med Genet B Neuropsychiatr Genet 132: 74–75.Google Scholar
  27. Gillberg, C (1998) Asperger syndrome and high-functioning autism. Br J Psychiatry 172: 200–209.CrossRefPubMedGoogle Scholar
  28. Graf, ER, Zhang, X, Jin, SX, Linhoff, MW and Craig, AM (2004) Neurexins induce differentiation of GABA and glutamate postsynaptic specializations via neuroligins. Cell 119: 1013–1026.CrossRefPubMedGoogle Scholar
  29. Ichtchenko, K, Hata, Y, Nguyen, T, Ullrich, B, Missler, M, Moomaw, C and Sudhof, TC (1995) Neuroligin 1: a splice site-specific ligand for beta-neurexins. Cell 81: 435–443.CrossRefPubMedGoogle Scholar
  30. Ichtchenko, K, Nguyen, T and Sudhof, TC (1996) Structures, alternative splicing, and neurexin binding of multiple neuroligins. J Biol Chem 271: 2676–2682.CrossRefPubMedGoogle Scholar
  31. Irie, M, Hata, Y, Takeuchi, M, Ichtchenko, K, Toyoda, A, Hirao, K, Takai, Y, Rosahl, TW and Sudhof, TC (1997) Binding of neuroligins to PSD-95. Science 277: 1511–1515.CrossRefPubMedGoogle Scholar
  32. 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) Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat Genet 34: 27–29.CrossRefPubMedGoogle Scholar
  33. Jamain, S, Radyushkin, K, Hammerschmidt, K, Granon, S, Boretius, S, Varoqueaux, F, Ramanantsoa, N, Gallego, J, Ronnenberg, A, Winter, D, 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.CrossRefPubMedGoogle Scholar
  34. Koehnke, J, Jin, X, Trbovic, N, Katsamba, PS, Brasch, J, Ahlsen, G, Scheiffele, P, Honig, B, Palmer, AG, 3rd, and Shapiro, L (2008) Crystal structures of beta-neurexin 1 and beta-neurexin 2 ectodomains and dynamics of splice insertion sequence 4. Structure 16: 410–421.CrossRefPubMedGoogle Scholar
  35. Laumonnier, F, Bonnet-Brilhault, F, Gomot, M, Blanc, R, David, A, Moizard, MP, Raynaud, M, Ronce, N, Lemonnier, E, Calvas, P, 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.CrossRefPubMedGoogle Scholar
  36. Levinson, JN, Chery, N, Huang, K, Wong, TP, Gerrow, K, Kang, R, Prange, O, Wang, YT and El-Husseini, A (2005) Neuroligins mediate excitatory and inhibitory synapse formation: involvement of PSD-95 and neurexin-1beta in neuroligin-induced synaptic specificity. J Biol Chem 280: 17312–17319.CrossRefPubMedGoogle Scholar
  37. Levinson, JN and El-Husseini, A (2005a) Building excitatory and inhibitory synapses: balancing neuroligin partnerships. Neuron 48: 171–174.CrossRefPubMedGoogle Scholar
  38. Levinson, JN and El-Husseini, A (2005b) New players tip the scales in the balance between excitatory and inhibitory synapses. Mol Pain 1: 12.CrossRefPubMedGoogle Scholar
  39. Meyer, G, Varoqueaux, F, Neeb, A, Oschlies, M and Brose, N (2004) The complexity of PDZ domain-mediated interactions at glutamatergic synapses: a case study on neuroligin. Neuropharmacology 47: 724–733.CrossRefPubMedGoogle Scholar
  40. Missler, M, Zhang, W, Rohlmann, A, Kattenstroth, G, Hammer, RE, Gottmann, K and Sudhof, TC (2003) Alpha-neurexins couple Ca2+ channels to synaptic vesicle exocytosis. Nature 423: 939–948.CrossRefPubMedGoogle Scholar
  41. Nam, CI and Chen, L (2005) Postsynaptic assembly induced by neurexin-neuroligin interaction and neurotransmitter. Proc Natl Acad Sci USA 102: 6137–6142.CrossRefPubMedGoogle Scholar
  42. Nguyen, T and Sudhof, TC (1997) Binding properties of neuroligin 1 and neurexin 1beta reveal function as heterophilic cell adhesion molecules. J Biol Chem 272: 26032–26039.CrossRefPubMedGoogle Scholar
  43. Penagarikano, O, Mulle, JG and Warren, ST (2007) The pathophysiology of fragile x syndrome. Annu Rev Genomics Hum Genet 8: 109–129.CrossRefPubMedGoogle Scholar
  44. Prange, O, Wong, TP, Gerrow, K, Wang, YT and El-Husseini, A (2004) A balance between excitatory and inhibitory synapses is controlled by PSD-95 and neuroligin. Proc Natl Acad Sci USA 101: 13915–13920.CrossRefPubMedGoogle Scholar
  45. Rubenstein, JL and Merzenich, MM (2003) Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav 2: 255–267.CrossRefPubMedGoogle Scholar
  46. Scheiffele, P, Fan, J, Choih, J, Fetter, R and Serafini, T (2000) Neuroligin expressed in nonneuronal cells triggers presynaptic development in contacting axons. Cell 101: 657–669.CrossRefPubMedGoogle Scholar
  47. Scholl, FG and Scheiffele, P (2003) Making connections: cholinesterase-domain proteins in the CNS. Trends Neurosci 26: 618–624.CrossRefPubMedGoogle Scholar
  48. Shen, KC, Kuczynska, DA, Wu, IJ, Murray, BH, Sheckler, LR and Rudenko, G (2008) Regulation of neurexin 1beta tertiary structure and ligand binding through alternative splicing. Structure 16: 422–431.CrossRefPubMedGoogle Scholar
  49. Song, JY, Ichtchenko, K, Sudhof, TC and Brose, N (1999) Neuroligin 1 is a postsynaptic cell-adhesion molecule of excitatory synapses. Proc Natl Acad Sci USA 96: 1100–1105.CrossRefPubMedGoogle Scholar
  50. Sudhof, TC (2001) alpha-Latrotoxin and its receptors: neurexins and CIRL/latrophilins. Annu Rev Neurosci 24: 933–962.CrossRefPubMedGoogle Scholar
  51. Sugita, S, Saito, F, Tang, J, Satz, J, Campbell, K and Sudhof, TC (2001) A stoichiometric complex of neurexins and dystroglycan in brain. J Cell Biol 154: 435–445.CrossRefPubMedGoogle Scholar
  52. Szatmari, P, Paterson, AD, Zwaigenbaum, L, Roberts, W, Brian, J, Liu, XQ, Vincent, JB, Skaug, JL, Thompson, AP, Senman, L, et al. (2007) Mapping autism risk loci using genetic linkage and chromosomal rearrangements. Nat Genet 39: 319–328.CrossRefPubMedGoogle Scholar
  53. Tabuchi, K, Blundell, J, Etherton, MR, Hammer, RE, Liu, X, Powell, CM and Sudhof, TC (2007) A neuroligin-3 mutation implicated in autism increases inhibitory synaptic transmission in mice. Science 318: 71–76.CrossRefPubMedGoogle Scholar
  54. Tabuchi, K and Sudhof, TC (2002) Structure and evolution of neurexin genes: insight into the mechanism of alternative splicing. Genomics 79: 849–859.CrossRefPubMedGoogle Scholar
  55. Talebizadeh, Z, Bittel, DC, Veatch, OJ, Butler, MG, Takahashi, TN and Miles, JH (2004) Do known mutations in neuroligin genes (NLGN3 and NLGN4) cause autism? J Autism Dev Disord 34: 735–736.CrossRefPubMedGoogle Scholar
  56. Taniguchi, H, Gollan, L, Scholl, FG, Mahadomrongkul, V, Dobler, E, Limthong, N, Peck, M, Aoki, C and Scheiffele, P (2007) Silencing of neuroligin function by postsynaptic neurexins. J Neurosci 27: 2815–2824.CrossRefPubMedGoogle Scholar
  57. Tzeng, MC and Siekevitz, P (1978) The effect of the purified major protein factor (alpha-latrotoxin) of black widow spider venom on the release of acetylcholine and norepinephrine from mouse cerebral cortex slices. Brain Res 139: 190–196.CrossRefPubMedGoogle Scholar
  58. Ullrich, B, Ushkaryov, YA and Sudhof, TC (1995) Cartography of neurexins: more than 1000 isoforms generated by alternative splicing and expressed in distinct subsets of neurons. Neuron 14: 497–507.CrossRefPubMedGoogle Scholar
  59. Ushkaryov, YA, Petrenko, AG, Geppert, M and Sudhof, TC (1992) Neurexins: synaptic cell surface proteins related to the alpha- latrotoxin receptor and laminin. Science 257: 50–56.CrossRefPubMedGoogle Scholar
  60. Varoqueaux, F, Aramuni, G, Rawson, RL, Mohrmann, R, Missler, M, Gottmann, K, Zhang, W, Sudhof, TC and Brose, N (2006) Neuroligins determine synapse maturation and function. Neuron 51: 741–754.CrossRefPubMedGoogle Scholar
  61. Varoqueaux, F, Jamain, S and Brose, N (2004) Neuroligin 2 is exclusively localized to inhibitory synapses. Eur J Cell Biol 83: 449–456.CrossRefPubMedGoogle Scholar
  62. Veenstra-Vanderweele, J, Cook, E, Jr., and Lombroso, PJ (2003) Genetics of childhood disorders: XLVI. Autism, part 5: genetics of autism. J Am Acad Child Adolesc Psychiatry 42: 116–118.CrossRefPubMedGoogle Scholar
  63. Veenstra-VanderWeele, J and Cook, EH, Jr. (2004) Molecular genetics of autism spectrum disorder. Mol Psychiatry 9: 819–832.CrossRefPubMedGoogle Scholar
  64. Vincent, JB, Kolozsvari, D, Roberts, WS, Bolton, PF, Gurling, HM and Scherer, SW (2004) Mutation screening of X-chromosomal neuroligin genes: no mutations in 196 autism probands. Am J Med Genet B Neuropsychiatr Genet 129: 82–84.CrossRefGoogle Scholar
  65. Yan, J, Oliveira, G, Coutinho, A, Yang, C, Feng, J, Katz, C, Sram, J, Bockholt, A., Jones, IR, Craddock, N, et al. (2005) Analysis of the neuroligin 3 and 4 genes in autism and other neuropsychiatric patients. Mol Psychiatry 10: 329–332.CrossRefPubMedGoogle Scholar
  66. Ylisaukko-oja, T, Rehnstrom, K, Auranen, M, Vanhala, R, Alen, R, Kempas, E, Ellonen, P, Turunen, JA, Makkonen, I, Riikonen, R, et al. (2005) Analysis of four neuroligin genes as candidates for autism. Eur J Hum Genet 13: 1285–1292.CrossRefPubMedGoogle Scholar
  67. Zoghbi, HY (2003) Postnatal neurodevelopmental disorders: meeting at the synapse? Science 302: 826–830.CrossRefPubMedGoogle Scholar
  68. Zoghbi, HY (2005) MeCP2 dysfunction in humans and mice. J Child Neurol 20: 736–740.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Departments of Neurology and PsychiatryThe University of Texas Southwestern Medical CenterDallasUSA
  2. 2.Department of Molecular and Cellular Physiology, Neurology and Psychiatry and Behavioral SciencesStanford UniversityPalo AltoUSA

Personalised recommendations