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Neurexins: molecular codes for shaping neuronal synapses

Abstract

The function of neuronal circuits relies on the properties of individual neuronal cells and their synapses. We propose that a substantial degree of synapse formation and function is instructed by molecular codes resulting from transcriptional programmes. Recent studies on the Neurexin protein family and its ligands provide fundamental insight into how synapses are assembled and remodelled, how synaptic properties are specified and how single gene mutations associated with neurodevelopmental and psychiatric disorders might modify the operation of neuronal circuits and behaviour. In this Review, we first summarize insights into Neurexin function obtained from various model organisms. We then discuss the mechanisms and logic of the cell type-specific regulation of Neurexin isoforms, in particular at the level of alternative mRNA splicing. Finally, we propose a conceptual framework for how combinations of synaptic protein isoforms act as ‘senders’ and ‘readers’ to instruct synapse formation and the acquisition of cell type-specific and synapse-specific functional properties.

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Fig. 1: Synaptogenic function of Neurexins.
Fig. 2: Molecular and structural features of Neurexin isoform diversity.
Fig. 3: Control of synapse specification by alternative splicing programmes.
Fig. 4: Examples of synaptic interaction modules nucleated by Neurexin proteins.
Fig. 5: Context-dependent functions of synaptic interaction modules.

References

  1. 1.

    Lu, W., Bushong, E. A., Shih, T. P., Ellisman, M. H. & Nicoll, R. A. The cell-autonomous role of excitatory synaptic transmission in the regulation of neuronal structure and function. Neuron 78, 433–439 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Sigler, A. et al. Formation and maintenance of functional spines in the absence of presynaptic glutamate release. Neuron 94, 304–311.e4 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Sando, R. et al. Assembly of excitatory synapses in the absence of glutamatergic neurotransmission. Neuron 94, 312–321.e3 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    Hobert, O. Terminal selectors of neuronal identity. Curr. Top. Dev. Biol. 116, 455–475 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  5. 5.

    Hassan, B. A. & Hiesinger, P. R. Beyond molecular codes: simple rules to wire complex brains. Cell 163, 285–291 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. 6.

    Sudhof, T. C. Synaptic Neurexin complexes: a molecular code for the logic of neural circuits. Cell 171, 745–769 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Sanes, J. R. & Zipursky, S. L. Synaptic specificity, recognition molecules, and assembly of neural circuits. Cell 181, 536–556 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  8. 8.

    Stoeckli, E. T. Understanding axon guidance: are we nearly there yet? Development https://doi.org/10.1242/dev.151415 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Dean, C. et al. Neurexin mediates the assembly of presynaptic terminals. Nat. Neurosci. 6, 708–716 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Scheiffele, P., Fan, J., Choih, J., Fetter, R. & Serafini, T. Neuroligin expressed in nonneuronal cells triggers presynaptic development in contacting axons. Cell 101, 657–669 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  11. 11.

    Dalva, M. B. et al. EphB receptors interact with NMDA receptors and regulate excitatory synapse formation. Cell 103, 945–956 (2000).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  12. 12.

    Graf, E. R., Zhang, X., Jin, S. X., Linhoff, M. W. & Craig, A. M. Neurexins induce differentiation of GABA and glutamate postsynaptic specializations via neuroligins. Cell 119, 1013–1026 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Chih, B., Gollan, L. & Scheiffele, P. Alternative splicing controls selective trans-synaptic interactions of the Neuroligin–Neurexin complex. Neuron 51, 171–178 (2006). Together with Graf et al. (2004), this study uncovers regulation of Neurexin synaptogenic activity by alternative splicing.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  14. 14.

    de Wit, J. et al. LRRTM2 interacts with Neurexin1 and regulates excitatory synapse formation. Neuron 64, 799–806 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  15. 15.

    Ko, J., Fuccillo, M. V., Malenka, R. C. & Sudhof, T. C. LRRTM2 functions as a Neurexin ligand in promoting excitatory synapse formation. Neuron 64, 791–798 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    Pettem, K. L. et al. The specific α-Neurexin interactor calsyntenin-3 promotes excitatory and inhibitory synapse development. Neuron 80, 113–128 (2013).

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Siddiqui, T. J., Pancaroglu, R., Kang, Y., Rooyakkers, A. & Craig, A. M. LRRTMs and Neuroligins bind Neurexins with a differential code to cooperate in glutamate synapse development. J. Neurosci. 30, 7495–7506 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    de Wit, J. & Ghosh, A. Specification of synaptic connectivity by cell surface interactions. Nat. Rev. Neurosci. 17, 22–35 (2016).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  19. 19.

    Missler, M. et al. α-Neurexins couple Ca2+ channels to synaptic vesicle exocytosis. Nature 423, 939–948 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  20. 20.

    Sudhof, T. C. Neuroligins and Neurexins link synaptic function to cognitive disease. Nature 455, 903–911 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  21. 21.

    Kurshan, P. T. et al. γ-Neurexin and frizzled mediate parallel synapse assembly pathways antagonized by receptor endocytosis. Neuron 100, 150–166.e4 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Maro, G. S. et al. MADD-4/punctin and Neurexin organize C. elegans GABAergic postsynapses through neuroligin. Neuron 86, 1420–1432 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    Philbrook, A. et al. Neurexin directs partner-specific synaptic connectivity in C. elegans. eLife 7, e35692 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    Hart, M. P. & Hobert, O. Neurexin controls plasticity of a mature, sexually dimorphic neuron. Nature 553, 165–170 (2018). This study uncovers a key role for Neurexin in structural plasticity in C. elegans.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Banovic, D. et al. Drosophila Neuroligin 1 promotes growth and postsynaptic differentiation at glutamatergic neuromuscular junctions. Neuron 66, 724–738 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  26. 26.

    Chen, Y. C. et al. Drosophila Neuroligin 2 is required presynaptically and postsynaptically for proper synaptic differentiation and synaptic transmission. J. Neurosci. 32, 16018–16030 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Li, J., Ashley, J., Budnik, V. & Bhat, M. A. Crucial role of Drosophila Neurexin in proper active zone apposition to postsynaptic densities, synaptic growth, and synaptic transmission. Neuron 55, 741–755 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Chen, S. X., Tari, P. K., She, K. & Haas, K. Neurexin–Neuroligin cell adhesion complexes contribute to synaptotropic dendritogenesis via growth stabilization mechanisms in vivo. Neuron 67, 967–983 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  29. 29.

    Constance, W. D. et al. Neurexin and Neuroligin-based adhesion complexes drive axonal arborisation growth independent of synaptic activity. eLife 7, e31659 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Burden, S. J., Huijbers, M. G. & Remedio, L. Fundamental molecules and mechanisms for forming and maintaining neuromuscular synapses. Int. J. Mol. Sci. 19, 490 (2018).

    PubMed Central  Article  CAS  Google Scholar 

  31. 31.

    Chen, L. Y., Jiang, M., Zhang, B., Gokce, O. & Sudhof, T. C. Conditional deletion of all Neurexins defines diversity of essential synaptic organizer functions for Neurexins. Neuron 94, 611–625 e614 (2017). This study highlights cell type-specific alterations in synapse formation and synaptic function resulting from genetic Neurexin deletion.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Takahashi, H. & Craig, A. M. Protein tyrosine phosphatases PTPδ, PTPσ, and LAR: presynaptic hubs for synapse organization. Trends Neurosci. 36, 522–534 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Li, Y. et al. Splicing-dependent trans-synaptic SALM3–LAR–RPTP interactions regulate excitatory synapse development and locomotion. Cell Rep. 12, 1618–1630 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. 34.

    Haklai-Topper, L. et al. The Neurexin superfamily of Caenorhabditis elegans. Gene Expr. Patterns 11, 144–150 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  35. 35.

    Knight, D., Xie, W. & Boulianne, G. L. Neurexins and Neuroligins: recent insights from invertebrates. Mol. Neurobiol. 44, 426–440 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Yan, Q. et al. Systematic discovery of regulated and conserved alternative exons in the mammalian brain reveals NMD modulating chromatin regulators. Proc. Natl Acad. Sci. USA 112, 1502849112 (2015).

    Google Scholar 

  37. 37.

    Nguyen, T. M. et al. An alternative splicing switch shapes Neurexin repertoires in principal neurons versus interneurons in the mouse hippocampus. eLife 5, e22757 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Ullrich, B., Ushkaryov, Y. A. & Sudhof, T. C. Cartography of Neurexins: more than 1000 isoforms generated by alternative splicing and expressed in distinct subsets of neurons. Neuron 14, 497–507 (1995).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  39. 39.

    Furlanis, E., Traunmuller, L., Fucile, G. & Scheiffele, P. Landscape of ribosome-engaged transcript isoforms reveals extensive neuronal-cell-class-specific alternative splicing programs. Nat. Neurosci. 22, 1709–1717 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Schreiner, D. et al. Targeted combinatorial alternative splicing generates brain region-specific repertoires of Neurexins. Neuron 84, 386–398 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  41. 41.

    Treutlein, B., Gokce, O., Quake, S. R. & Südhof, T. C. Cartography of Neurexin alternative splicing mapped by single-molecule long-read mRNA sequencing. Proc. Natl Acad. Sci. USA 111, E1291–E1299 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  42. 42.

    Flaherty, E. et al. Neuronal impact of patient-specific aberrant NRXN1α splicing. Nat. Genet. 51, 1679–1690 (2019). Together with Schreiner et al. (2014) and Treutlein et al. (2014), this study reports numbers and cell type-selectivity of Neurexin splice isoforms in rodent and human neurons by long-read mRNA sequencing.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Ding, X. et al. Translational inhibition of α-Neurexin 2. Sci. Rep. 10, 3403 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Schreiner, D., Simicevic, J., Ahrné, E., Schmidt, A. & Scheiffele, P. Quantitative isoform-profiling of highly diversified recognition molecules. eLife 4, 1–17 (2015).

    Article  Google Scholar 

  45. 45.

    Ushkaryov, Y. A., Petrenko, A. G., Geppert, M. & Sudhof, T. C. Neurexins: synaptic cell surface proteins related to the α-latrotoxin receptor and laminin. Science 257, 50–56 (1992).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  46. 46.

    Comoletti, D. et al. The macromolecular architecture of extracellular domain of αNRXN1: domain organization, flexibility, and insights into trans-synaptic disposition. Structure 18, 1044–1053 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Biederer, T. & Sudhof, T. C. CASK and protein 4.1 support F-actin nucleation on Neurexins. J. Biol. Chem. 276, 47869–47876 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  48. 48.

    Miller, M. T. et al. The crystal structure of the α-Neurexin-1 extracellular region reveals a hinge point for mediating synaptic adhesion and function. Structure 19, 767–778 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Sheckler, L. R., Henry, L., Sugita, S., Sudhof, T. C. & Rudenko, G. Crystal structure of the second LNS/LG domain from Neurexin 1α: Ca2+ binding and the effects of alternative splicing. J. Biol. Chem. 281, 22896–22905 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Wilson, S. C. et al. Structures of Neurexophilin–Neurexin complexes reveal a regulatory mechanism of alternative splicing. EMBO J. 38, e101603 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51.

    Rudenko, G., Hohenester, E. & Muller, Y. A. LG/LNS domains: multiple functions — one business end? Trends Biochem. Sci. 26, 363–368 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  52. 52.

    Arac, D. et al. Structures of Neuroligin-1 and the Neuroligin-1/Neurexin-1β complex reveal specific protein–protein and protein–Ca2+ interactions. Neuron 56, 992–1003 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  53. 53.

    Chen, X., Liu, H., Shim, A. H., Focia, P. J. & He, X. Structural basis for synaptic adhesion mediated by Neuroligin–Neurexin interactions. Nat. Struct. Mol. Biol. 15, 50–56 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  54. 54.

    Fabrichny, I. P. et al. Structural analysis of the synaptic protein Neuroligin and its β-Neurexin complex: determinants for folding and cell adhesion. Neuron 56, 979–991 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    Koehnke, J. et al. Crystal structure of the extracellular cholinesterase-like domain from Neuroligin-2. Proc. Natl Acad. Sci. USA 105, 1873–1878 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  56. 56.

    Koehnke, J. et al. Crystal structures of β-Neurexin 1 and β-Neurexin 2 ectodomains and dynamics of splice insertion sequence 4. Structure 16, 410–421 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Boucard, A. A., Chubykin, A. A., Comoletti, D., Taylor, P. & Sudhof, T. C. A splice code for trans-synaptic cell adhesion mediated by binding of Neuroligin 1 to α- and β-Neurexins. Neuron 48, 229–236 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  58. 58.

    Koehnke, J. et al. Splice form dependence of β-Neurexin/Neuroligin binding interactions. Neuron 67, 61–74 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Uemura, T. et al. Trans-synaptic interaction of GluRδa2 and Neurexin through Cbln1 mediates synapse formation in the cerebellum. Cell 141, 1068–1079 (2010). This study discovers a tripartite synaptic complex consisting of Neurexins, Cerebellins and the postsynaptic receptor GLUD2.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  60. 60.

    Zhang, P. et al. Heparan sulfate organizes neuronal synapses through Neurexin partnerships. Cell 174, 1450–1464.e23 (2018). This work reveals a major contribution of Neurexin carbohydrate modifications to the assembly of synaptic protein complexes.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61.

    Roppongi, R. T. et al. LRRTMs organize synapses through differential engagement of Neurexin and PTPσ. Neuron 106, 108–125.e12 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  62. 62.

    Bulow, H. E. & Hobert, O. The molecular diversity of glycosaminoglycans shapes animal development. Annu. Rev. Cell Dev. Biol. 22, 375–407 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  63. 63.

    Sugita, S. et al. A stoichiometric complex of Neurexins and dystroglycan in brain. J. Cell Biol. 154, 435–445 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. 64.

    Chen, F., Venugopal, V., Murray, B. & Rudenko, G. The structure of Neurexin 1α reveals features promoting a role as synaptic organizer. Structure 19, 779–789 (2011). Together with Miller et al. (2011), this study uncovers the structural organization of the α-Neurexin extracellular domain.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 65.

    Tanaka, H. et al. Higher-order architecture of cell adhesion mediated by polymorphic synaptic adhesion molecules Neurexin and Neuroligin. Cell Rep. 2, 101–110 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  66. 66.

    Fuccillo, M. V. et al. Single-cell mRNA profiling reveals cell-type-specific expression of Neurexin isoforms. Neuron 87, 326–340 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. 67.

    Lukacsovich, D. et al. Single-cell RNA-seq reveals developmental origins and ontogenetic stability of Neurexin alternative splicing profiles. Cell Rep. 27, 3752–3759.e4 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  68. 68.

    Winterer, J. et al. Single-cell RNA-seq characterization of anatomically identified OLM interneurons in different transgenic mouse lines. Eur. J. Neurosci. 50, 3750–3771 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    Chen, M. & Manley, J. L. Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches. Nat. Rev. Mol. Cell Biol. 10, 741–754 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70.

    Neugebauer, K. M. Nascent RNA and the coordination of splicing with transcription. Cold Spring Harb. Perspect. Biol. https://doi.org/10.1101/cshperspect.a032227 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Raj, B. & Blencowe, B. J. Alternative splicing in the mammalian nervous system: recent insights into mechanisms and functional roles. Neuron 87, 14–27 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  72. 72.

    Darnell, R. B. RNA protein interaction in neurons. Annu. Rev. Neurosci. 36, 243–270 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. 73.

    Resnick, M., Segall, A., G, G. R., Lupowitz, Z. & Zisapel, N. Alternative splicing of Neurexins: a role for neuronal polypyrimidine tract binding protein. Neurosci. Lett. 439, 235–240 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  74. 74.

    Gehman, L. T. et al. The splicing regulator Rbfox2 is required for both cerebellar development and mature motor function. Genes Dev. 26, 445–460 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. 75.

    Saito, Y. et al. Differential NOVA2-mediated splicing in excitatory and inhibitory neurons regulates cortical development and cerebellar function. Neuron 101, 707–720.e5 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. 76.

    Wamsley, B. et al. Rbfox1 mediates cell-type-specific splicing in cortical interneurons. Neuron 100, 846–859 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. 77.

    Di Fruscio, M., Chen, T. & Richard, S. Characterization of Sam68-like mammalian proteins SLM-1 and SLM-2: SLM-1 is a Src substrate during mitosis. Proc. Natl Acad. Sci. USA 96, 2710–2715 (1999).

    PubMed  Article  PubMed Central  Google Scholar 

  78. 78.

    Feracci, M. et al. Structural basis of RNA recognition and dimerization by the STAR proteins T-STAR and Sam68. Nat. Commun. 7, 10355 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. 79.

    Danilenko, M. et al. Binding site density enables paralog-specific activity of SLM2 and Sam68 proteins in Neurexin2 AS4 splicing control. Nucleic Acids Res. 45, 4120–4130 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Iijima, T., Iijima, Y., Witte, H. & Scheiffele, P. Neuronal cell type-specific alternative splicing is regulated by the KH domain protein SLM1. J. Cell Biol. 204, 331–342 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. 81.

    Iijima, T. et al. SAM68 regulates neuronal activity-dependent alternative splicing of Neurexin-1. Cell 147, 1601–1614 (2011). This study discovers the regulation of neuronal activity-dependent alternative splicing of Neurexins by the STAR family RNA-binding protein SAM68.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. 82.

    Elegheert, J. et al. Structural basis for integration of GluD receptors within synaptic organizer complexes. Science 353, 295–299 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. 83.

    Matsuda, K. & Yuzaki, M. Cbln family proteins promote synapse formation by regulating distinct Neurexin signaling pathways in various brain regions. Eur. J. Neurosci. 33, 1447–1461 (2011).

    PubMed  Article  PubMed Central  Google Scholar 

  84. 84.

    Ito-Ishida, A. et al. Cbln1 regulates rapid formation and maintenance of excitatory synapses in mature cerebellar Purkinje cells in vitro and in vivo. J. Neurosci. 28, 5920–5930 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. 85.

    Matsuda, K. et al. Cbln1 is a ligand for an orphan glutamate receptor δ2, a bidirectional synapse organizer. Science 328, 363–368 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  86. 86.

    Stoss, O. et al. p59fyn-mediated phosphorylation regulates the activity of the tissue-specific splicing factor rSLM-1. Mol. Cell Neurosci. 27, 8–21 (2004).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  87. 87.

    Traunmüller, L., Bornmann, C. & Scheiffele, P. Alternative splicing coupled nonsense-mediated decay generates neuronal cell type-specific expression of SLM proteins. J. Neurosci. 34, 16755–16761 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  88. 88.

    Ehrmann, I. et al. The tissue-specific RNA binding protein T-STAR controls regional splicing patterns of Neurexin pre-mRNAs in the brain. PLoS Genet. 9, e1003474 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. 89.

    Traunmüller, L., Gomez, A. M., Nguyen, T.-M. & Scheiffele, P. Control of neuronal synapse specification by highly dedicated alternative splicing program. Science 352, 982–986 (2016).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  90. 90.

    Aoto, J., Martinelli, D. C., Malenka, R. C., Tabuchi, K. & Südhof, T. C. Presynaptic Neurexin-3 alternative splicing trans-synaptically controls postsynaptic AMPA receptor trafficking. Cell 154, 75–88 (2013). Together with Traunmüller et al. (2016), this study demonstrates a major impact of Neurexin alternative splicing on glutamatergic synapse function.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. 91.

    Chubykin, A. A. et al. Activity-dependent validation of excitatory versus inhibitory synapses by Neuroligin-1 versus Neuroligin-2. Neuron 54, 919–931 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. 92.

    Shipman, S. L. & Nicoll, R. A. A subtype-specific function for the extracellular domain of Neuroligin 1 in hippocampal LTP. Neuron 76, 309–316 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. 93.

    Soler-Llavina, G. J. et al. Leucine-rich repeat transmembrane proteins are essential for maintenance of long-term potentiation. Neuron 79, 439–446 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. 94.

    Dai, J., Aoto, J. & Sudhof, T. C. Alternative splicing of presynaptic Neurexins differentially controls postsynaptic NMDA and AMPA receptor responses. Neuron 102, 993–1008.e5 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  95. 95.

    Matsuda, K. et al. Transsynaptic modulation of kainate receptor functions by C1q-like proteins. Neuron 90, 752–767 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  96. 96.

    Quesnel-Vallieres, M. et al. Misregulation of an activity-dependent splicing network as a common mechanism underlying autism spectrum disorders. Mol. Cell 64, 1023–1034 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  97. 97.

    Xie, J. & Black, D. L. A CaMK IV responsive RNA element mediates depolarization-induced alternative splicing of ion channels. Nature 410, 936–939 (2001).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  98. 98.

    Rozic-Kotliroff, G. & Zisapel, N. Ca2+-dependent splicing of Neurexin IIα. Biochem. Biophys. Res. Commun. 352, 226–230 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  99. 99.

    Ding, X. et al. Activity-induced histone modifications govern Neurexin-1 mRNA splicing and memory preservation. Nat. Neurosci. 20, 690–699 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  100. 100.

    Saura, C. A., Servian-Morilla, E. & Scholl, F. G. Presenilin/γ-secretase regulates Neurexin processing at synapses. PLoS ONE 6, e19430 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. 101.

    Servian-Morilla, E. et al. Proteolytic processing of Neurexins by presenilins sustains synaptic vesicle release. J. Neurosci. 38, 901–917 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. 102.

    Lim, L. et al. Optimization of interneuron function by direct coupling of cell migration and axonal targeting. Nat. Neurosci. 21, 920–931 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  103. 103.

    Kornblihtt, A. R. Transcriptional control of alternative splicing along time: ideas change, experiments remain. RNA 21, 670–672 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. 104.

    Furlanis, E. & Scheiffele, P. Regulation of neuronal differentiation, function, and plasticity by alternative splicing. Annu. Rev. Cell Dev. Biol. 34, 451–469 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. 105.

    Tanabe, Y. et al. IgSF21 promotes differentiation of inhibitory synapses via binding to Neurexin2α. Nat. Commun. 8, 408 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  106. 106.

    Hu, Z., Xiao, X., Zhang, Z. & Li, M. Genetic insights and neurobiological implications from NRXN1 in neuropsychiatric disorders. Mol. Psychiatry 24, 1400–1414 (2019).

    PubMed  Article  PubMed Central  Google Scholar 

  107. 107.

    Castronovo, P. et al. Phenotypic spectrum of NRXN1 mono- and bi-allelic deficiency: a systematic review. Clin. Genet. 97, 125–137 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  108. 108.

    Cosemans, N. et al. The clinical relevance of intragenic NRXN1 deletions. J. Med. Genet. 57, 347–355 (2020).

    PubMed  Article  PubMed Central  Google Scholar 

  109. 109.

    Rujescu, D. et al. Disruption of the Neurexin 1 gene is associated with schizophrenia. Hum. Mol. Genet. 18, 988–996 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  110. 110.

    Vaags, A. K. et al. Rare deletions at the Neurexin 3 locus in autism spectrum disorder. Am. J. Hum. Genet. 90, 133–141 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. 111.

    Huang, A. Y. et al. Rare copy number variants in NRXN1 and CNTN6 increase risk for Tourette syndrome. Neuron 94, 1101–1111.e7 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  112. 112.

    Nussbaum, J. et al. Significant association of the Neurexin-1 gene (NRXN1) with nicotine dependence in European- and African-American smokers. Hum. Mol. Genet. 17, 1569–1577 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. 113.

    Rochtus, A. M. et al. Mutations in NRXN1 and NRXN2 in a patient with early-onset epileptic encephalopathy and respiratory depression. Cold Spring Harb. Mol. Case Stud. 5, a003442 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  114. 114.

    Redon, R. et al. Global variation in copy number in the human genome. Nature 444, 444–454 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. 115.

    Bena, F. et al. Molecular and clinical characterization of 25 individuals with exonic deletions of NRXN1 and comprehensive review of the literature. Am. J. Med. Genet. B Neuropsychiatr. Genet 162B, 388–403 (2013).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  116. 116.

    Vinas-Jornet, M. et al. A common cognitive, psychiatric, and dysmorphic phenotype in carriers of NRXN1 deletion. Mol. Genet. Genomic Med. 2, 512–521 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  117. 117.

    Harrison, V. et al. Compound heterozygous deletion of NRXN1 causing severe developmental delay with early onset epilepsy in two sisters. Am. J. Med. Genet. A 155A, 2826–2831 (2011).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  118. 118.

    Zweier, C. et al. CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt–Hopkins-like mental retardation and determine the level of a common synaptic protein in Drosophila. Am. J. Hum. Genet. 85, 655–666 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. 119.

    Gillberg, C. The ESSENCE in child psychiatry: early symptomatic syndromes eliciting neurodevelopmental clinical examinations. Res. Dev. Disabil. 31, 1543–1551 (2010).

    PubMed  Article  PubMed Central  Google Scholar 

  120. 120.

    Tong, X. J., Hu, Z., Liu, Y., Anderson, D. & Kaplan, J. M. A network of autism linked genes stabilizes two pools of synaptic GABAA receptors. eLife 4, e09648 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  121. 121.

    Etherton, M. R., Blaiss, C. A., Powell, C. M. & Sudhof, T. C. Mouse Neurexin-1α deletion causes correlated electrophysiological and behavioral changes consistent with cognitive impairments. Proc. Natl Acad. Sci. USA 106, 17998–18003 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  122. 122.

    Laarakker, M. C., Reinders, N. R., Bruining, H., Ophoff, R. A. & Kas, M. J. Sex-dependent novelty response in Neurexin-1α mutant mice. PLoS ONE 7, e31503 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  123. 123.

    Esclassan, F., Francois, J., Phillips, K. G., Loomis, S. & Gilmour, G. Phenotypic characterization of nonsocial behavioral impairment in Neurexin 1α knockout rats. Behav. Neurosci. 129, 74–85 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  124. 124.

    Dachtler, J. et al. Deletion of α-Neurexin II results in autism-related behaviors in mice. Transl. Psychiatry 4, e484 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  125. 125.

    Dachtler, J. et al. Heterozygous deletion of α-Neurexin I or α-Neurexin II results in behaviors relevant to autism and schizophrenia. Behav. Neurosci. 129, 765–776 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  126. 126.

    Born, G. et al. Genetic targeting of NRXN2 in mice unveils role in excitatory cortical synapse function and social behaviors. Front. Synaptic Neurosci. 7, 3 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  127. 127.

    Rabaneda, L. G., Robles-Lanuza, E., Nieto-Gonzalez, J. L. & Scholl, F. G. Neurexin dysfunction in adult neurons results in autistic-like behavior in mice. Cell Rep. 8, 338–346 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  128. 128.

    Greenberg, D. M., Warrier, V., Allison, C. & Baron-Cohen, S. Testing the empathizing–systemizing theory of sex differences and the extreme male brain theory of autism in half a million people. Proc. Natl Acad. Sci. USA 115, 12152–12157 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  129. 129.

    Keum, S. et al. A missense variant at the Nrxn3 locus enhances empathy fear in the mouse. Neuron 98, 588–601 e585 (2018). This study reports the critical contribution of a Nrxn3 sequence variant in mice to cortical circuit function and emotional behaviour.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  130. 130.

    Panksepp, J. & Panksepp, J. B. Toward a cross-species understanding of empathy. Trends Neurosci. 36, 489–496 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  131. 131.

    Cao, Y. et al. Mechanism for selective synaptic wiring of rod photoreceptors into the retinal circuitry and its role in vision. Neuron 87, 1248–1260 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. 132.

    Sylwestrak, E. L. & Ghosh, A. Elfn1 regulates target-specific release probability at CA1–interneuron synapses. Science 338, 536–540 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  133. 133.

    Tomioka, N. H. et al. Elfn1 recruits presynaptic mGluR7 in trans and its loss results in seizures. Nat. Commun. 5, 4501 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  134. 134.

    Park, H. et al. Splice-dependent trans-synaptic PTPδ–IL1RAPL1 interaction regulates synapse formation and non-REM sleep. EMBO J. 39, e104150 (2020). This work uncovers a key role for an alternative exon in the regulation of trans-synaptic interactions, synaptic transmission and mouse behaviour.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  135. 135.

    Kim, K. et al. Presynaptic PTPσ regulates postsynaptic NMDA receptor function through direct adhesion-independent mechanisms. eLife 9, e54224 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  136. 136.

    Shen, K. & Scheiffele, P. Genetics and cell biology of building specific synaptic connectivity. Annu. Rev. Neurosci. 33, 473–507 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  137. 137.

    Kim, B. & Emmons, S. W. Multiple conserved cell adhesion protein interactions mediate neural wiring of a sensory circuit in C. elegans. eLife 6, e29257 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  138. 138.

    Schroeder, A. et al. A modular organization of LRR protein-mediated synaptic adhesion defines synapse identity. Neuron 99, 329–344.e7 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  139. 139.

    Yamagata, A. et al. Structural insights into modulation and selectivity of transsynaptic Neurexin–LRRTM interaction. Nat. Commun. 9, 3964 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  140. 140.

    Ibata, K. et al. Activity-dependent secretion of synaptic organizer Cbln1 from lysosomes in granule cell axons. Neuron 102, 1184–1198.10 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  141. 141.

    Ito-Ishida, A. et al. Presynaptically released Cbln1 induces dynamic axonal structural changes by interacting with GluD2 during cerebellar synapse formation. Dev. Cell 23, 923–924 (2012). Together with Matsuda et al. (2010), this study demonstrates critical in vivo functions of the Neurexin–Cerebellin–GLUD2 complex in cerebellar synapse formation and maintenance.

    Article  CAS  Google Scholar 

  142. 142.

    Brockhaus, J. et al. α-Neurexins together with α2δ-1 auxiliary subunits regulate Ca2+ influx through Cav2.1 channels. J. Neurosci. 38, 8277–8294 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  143. 143.

    Tong, X. J. et al. Retrograde synaptic inhibition is mediated by α-Neurexin binding to the α2δ subunits of N-type calcium channels. Neuron 95, 326–340.e5 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  144. 144.

    Hrvatin, S. et al. Single-cell analysis of experience-dependent transcriptomic states in the mouse visual cortex. Nat. Neurosci. 21, 120–129 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  145. 145.

    Uchigashima, M., Cheung, A., Suh, J., Watanabe, M. & Futai, K. Differential expression of Neurexin genes in the mouse brain. J. Comp. Neurol. 527, 1940–1965 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  146. 146.

    Venkatesh, H. S. et al. Targeting neuronal activity-regulated neuroligin-3 dependency in high-grade glioma. Nature 549, 533–537 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  147. 147.

    Venkataramani, V. et al. Glutamatergic synaptic input to glioma cells drives brain tumour progression. Nature 573, 532–538 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  148. 148.

    Zeng, Q. et al. Synaptic proximity enables NMDAR signalling to promote brain metastasis. Nature 573, 526–531 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  149. 149.

    Stogsdill, J. A. et al. Astrocytic neuroligins control astrocyte morphogenesis and synaptogenesis. Nature 551, 192–197 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  150. 150.

    Singh, S. K. et al. Astrocytes assemble thalamocortical synapses by bridging NRX1α and NL1 via Hevin. Cell 164, 183–196 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  151. 151.

    Xu, J., Xiao, N. & Xia, J. Thrombospondin 1 accelerates synaptogenesis in hippocampal neurons through neuroligin 1. Nat. Neurosci. 13, 22–24 (2009).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

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Acknowledgements

A.M.G. was financially supported by an advanced European Molecular Biology Organization (EMBO) long-term fellowship. L.T. was supported by the Boehringer Ingelheim Fonds and the Doris Dietschy and Denise Dietschy-Frick-Stiftung. Work in the laboratory of P.S. is supported by the Swiss National Science Foundation, a European Research Council Advanced Grant (SPLICECODE), and EU-AIMS and AIMS-2-TRIALS supported by the Innovative Medicines Initiatives from the European Commission. This joint undertaking receives support from the European Union’s Horizon 2020 research and innovation programme, the European Federation of Pharmaceutical Industries and Associates (EFPIA), Autism Speaks, Autistica and the Simons Foundation Autism Research Initiative (SFARI).

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Glossary

Alternative splicing

A process in which exons of an mRNA are assembled in multiple different (alternative) ways to yield multiple different versions of a final mRNA molecule that may contain different RNA regulatory motifs or encode alternative protein forms.

Isoforms

Variants of an mRNA transcript or protein generated from a single gene but differing in sequence (for example, resulting from alternative promoters or from alternative splicing).

Post-translational modifications

Enzymatic chemical modifications of specific amino acids in a protein that occur in the cell after or during mRNA translation (for example, through phosphorylation, glycosylation, acetylation and so on).

Structural motifs

Structurally conserved building blocks or ‘super-secondary structures’ that appear in various protein molecules that may or may not be functionally related.

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Gomez, A.M., Traunmüller, L. & Scheiffele, P. Neurexins: molecular codes for shaping neuronal synapses. Nat Rev Neurosci 22, 137–151 (2021). https://doi.org/10.1038/s41583-020-00415-7

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