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  • Review Article
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Glycans and neural cell interactions

Nature Reviews Neuroscience volume 5, pages 195–208 (2004)Cite this article

Key Points

  • Glycans (chains of monosaccharides) are becoming increasingly recognized as participants in neural cell interactions in the developing and adult nervous system. They are involved in diverse functions that depend on cell recognition, such as cell migration, neurite outgrowth and fasciculation, synapse formation and stabilization, and modulation of synaptic efficacy.

  • The addition of monosaccharides in different configurations to ceramide leads to the formation of various glycolipids. Glycoproteins, proteoglycans and mucins carry glycans that are covalently attached to protein backbones in various linkages. There are two broad groups of glycoproteins — N-glycans and O-glycans — which differ in their nature of the linkage to the protein backbone.

  • Polysialic acid is carried by the neural cell adhesion molecule NCAM. It decreases homophilic NCAM-mediated interactions and is an important ingredient in NCAM's functions: for instance, it enhances migration of neural stem cells, promotes neurite outgrowth and is involved in regenerative processes after trauma and synaptic plasticity during learning and memory.

  • Oligomannosides are usually transient biosynthetic appendices of N-linked carbohydrates on glycoproteins en route to the cell surface and the extracellular matrix. In most tissues, oligomannosides are eliminated during the processing of sugars to yield mature N-glycans, but predominantly in the brain, they are carried to the cell surface on recognition molecules.

  • In the nervous system, myelin-associated glycoprotein (MAG) was the first molecule that was shown to bind α2,3-linked sialic acid. MAG is involved not only in myelin formation, but also in myelin maintenance. It has received particular attention because it enhances in vitro neurite outgrowth at early developmental stages, but inhibits neurite outgrowth in the adult.

  • The human natural killer cell glycan HNK1 is found on glycolipids and glycoproteins, and it is the target epitope for auto-antibodies in severe peripheral neuropathies. Several receptors for HNK1 with roles in development have been identified in the nervous system, and HNK1 has also been implicated in synaptic plasticity and motor neuron regeneration.

  • Glycosaminoglycans are long repeating linear polymers of disaccharides. The main glycosaminoglycans in the brain are chondroitin sulphates and heparan sulphates, which are carried by different protein backbones. Chondroitin sulphate proteoglycans and hyaluronan (a large polymer consisting of alternating glucuronic acid and N-acetylglucosamine residues) are localized in perineuronal nets, which are believed to be crucial for regulating synaptic efficacy.

  • Chondroitin sulphate is a repellent for growth cones, acting as a molecular barrier, particularly in choice situations. Removal of chondroitin sulphate chains from proteoglycans reduces their barrier functions and allows regrowth of severed axons and synaptic rearrangements.

  • Glycans have been shown to have pivotal roles in nervous system development, regeneration and synaptic plasticity. Owing to their structural richness, they could be as versatile as the protein backbone that carries them.

Abstract

Carbohydrate-carrying molecules in the nervous system have important roles during development, regeneration and synaptic plasticity. Carbohydrates mediate interactions between recognition molecules, thereby contributing to the formation of a complex molecular meshwork at the cell surface and in the extracellular matrix. The tremendous structural diversity of glycan chains allows for immense combinatorial possibilities that might underlie the fine-tuning of cell–cell and cell–matrix interactions.

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Figure 1: Biosynthesis of glycolipids.
Figure 2: Biosynthesis of N-glycans.
Figure 3: Biosynthesis of O-glycans.
Figure 4: Polysialic acid (PSA) and its carriers.
Figure 5: Oligomannosidic glycans.
Figure 6: Putative α2,3-sialic acid binding motif in recognition molecules.
Figure 7: HNK1 carbohydrate.
Figure 8: Glycosaminoglycans on proteoglycans.

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References

  1. Finne, J., Finne, U., Deagostini-Bazin, H. & Goridis, C. Occurrence of α2-8 linked polysialosyl units in a neural cell adhesion molecule. Biochem. Biophys. Res. Commun. 112, 482–487 (1983).

    Article  CAS  PubMed  Google Scholar 

  2. Eckhardt, M. et al. Mice deficient in the polysialyltransferase ST8SiaIV/PST-1 allow discrimination of the roles of neural cell adhesion molecule protein and polysialic acid in neural development and synaptic plasticity. J. Neurosci. 20, 5234–5244 (2000). Mice deficient in this polysialyltransferase allow the dissection of developmentally early and late functions of polysialic acid.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. von der Ohe, M. et al. Localization and characterization of polysialic acid-containing N-linked glycans from bovine NCAM. Glycobiology 12, 47–63 (2002).

    Article  CAS  PubMed  Google Scholar 

  4. Rutishauser, U. & Landmesser, L. Polysialic acid in the vertebrate nervous system: a promoter of plasticity in cell–cell interactions. Trends Neurosci. 19, 422–427 (1996). An early review highlighting the seminal work on polysialic acid-dependent axon branching and fasciculation in the peripheral nervous system.

    Article  CAS  PubMed  Google Scholar 

  5. Sadoul, R., Hirn, M., Deagostini-Bazin, H., Rougon, G. & Goridis, C. Adult and embryonic mouse neural cell adhesion molecules have different binding properties. Nature 304, 347–349 (1983).

    Article  CAS  PubMed  Google Scholar 

  6. Cunningham, B. A., Hoffman, S., Rutishauser, U., Hemperly, J. J. & Edelman, G. M. Molecular topography of the neural cell adhesion molecule N-CAM: surface orientation and location of sialic acid-rich and binding regions. Proc. Natl Acad. Sci. USA 80, 3116–3120 (1983).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Yang, P., Major, D. & Rutishauser, U. Role of charge and hydration in effects of polysialic acid on molecular interactions on and between cell membranes. J. Biol. Chem. 269, 23039–23044 (1994).

    CAS  PubMed  Google Scholar 

  8. Storms, S. D. & Rutishauser, U. A role for polysialic acid in neural cell adhesion molecule heterophilic binding to proteoglycans. J. Biol. Chem. 273, 27124–27129 (1998).

    Article  CAS  PubMed  Google Scholar 

  9. Durbec, P. & Cremer, H. Revisiting the function of PSA-NCAM in the nervous system. Mol. Neurobiol. 24, 53–64 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Yamamoto, N. et al. Inhibitory mechanism by polysialic acid for lamina-specific branch formation of thalamocortical axons. J. Neurosci. 20, 9145–9151 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Muller, D., Stoppini, L., Wang, C. & Kiss, J. Z. A role for polysialylated neural cell adhesion molecule in lesion-induced sprouting in hippocampal organotypic cultures. Neuroscience 61, 441–445 (1994).

    Article  CAS  PubMed  Google Scholar 

  12. Seiki, T. Microenvironmental elements supporting adult hippocampal neurogenesis. Anat. Sci. Int. 78, 69–78 (2003).

    Article  Google Scholar 

  13. Kempermann, G., Gast, D. & Gage, F. H. Neuroplasticity in old age: sustained fivefold induction of hippocampal neurogenesis by long-term environmental enrichment. Ann. Neurol. 52, 135–143 (2002).

    Article  PubMed  Google Scholar 

  14. Hekmat, A., Bitter-Suermann, D. & Schachner, M. Immunocytological localization of the highly polysialylated form of the neural cell adhesion molecule during development of the murine cerebellar cortex. J. Comp. Neurol. 291, 457–467 (1990).

    Article  CAS  PubMed  Google Scholar 

  15. Hu, H. Polysialic acid regulates chain formation by migrating olfactory interneuron precursors. J. Neurosci. Res. 61, 480–492 (2000).

    Article  CAS  PubMed  Google Scholar 

  16. Chazal, G., Durbec, P., Jankovski, A., Rougon, G. & Cremer, H. Consequences of neural cell adhesion molecule deficiency on cell migration in the rostral migratory stream of the mouse. J. Neurosci. 20, 1446–1457 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Piet, R., Poulain, D. A. & Oliet, S. H. Modulation of synaptic transmission by astrocytes in the rat supraoptic nucleus. J. Physiol. (Paris) 96, 231–236 (2002).

    Article  CAS  Google Scholar 

  18. Theodosis, D. T., Bonhomme, R., Vitiello, S., Rougon, G. & Poulain, D. A. Cell surface expression of polysialic acid on NCAM is a prerequisite for activity-dependent morphological neuronal and glial plasticity. J. Neurosci. 19, 10228–10236 (1999). This study describes the role of polysialic acid in structure and function of the hypothalamo-neurohypophysial system.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Prosser, R. A., Rutishauser, U., Ungers, G., Fedorkova, L. & Glass, J. D. Intrinsic role of polysialylated neural cell adhesion molecule in photic phase resetting of the mammalian circadian clock. J. Neurosci. 23, 652–658 (2003) This paper is the most recent account on the fascinating role of polysialic acid in regulating the circadian clock.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Fox, G. B., O'Connell, A. W., Murphy, K. J. & Regan, C. M. Memory consolidation induces a transient and time-dependent increase in the frequency of neural cell adhesion molecule polysialylated cells in the adult rat hippocampus. J. Neurochem. 65, 2796–2799 (1995).

    Article  CAS  PubMed  Google Scholar 

  21. Becker, C. G. et al. The polysialic acid modification of the neural cell adhesion molecule is involved in spatial learning and hippocampal long-term potentiation. J. Neurosci. Res. 45, 143–152 (1996).

    Article  CAS  PubMed  Google Scholar 

  22. Muller, D. et al. PSA-NCAM is required for activity-induced synaptic plasticity. Neuron 17, 413–422 (1996).

    Article  CAS  PubMed  Google Scholar 

  23. Suppiramaniam, V. et al. Colominic acid (polysialic acid) alters the channel properties of AMPA receptors reconstituted in lipid bilayers. Soc. Neurosci. Abstr. 25, 1489 (1999).

    Google Scholar 

  24. Toni, N. et al. Long-term potentiation in the CA1 hippocampal formation may induce synaptogenesis by splitting of activated synapses. 30th Annu. Meet. Swiss Soc. Exp. Bio. Abstr. S6–22 (1998).

  25. Bruses, J. L. & Rutishauser, U. Regulation of neural cell adhesion molecule polysialylation: evidence for nontranscriptional control and sensitivity to an intracellular pool of calcium. J. Cell Biol. 140, 1177–1186 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rusakov, D. A., Davies, H. A., Krivko, I. M., Stewart, M. G. & Schachner, M. Training in chicks alters PSA-N-CAM distribution in forebrain cell membranes. Neuroreport 5, 2469–2473 (1994).

    Article  CAS  PubMed  Google Scholar 

  27. Rusakov, D. A., Davies, H. A., Stewart, M. G. & Schachner, M. Clustering and co-localization of immunogold double labelled neural cell adhesion molecule isoforms in chick forebrain. Neurosci. Lett. 183, 50–53 (1995).

    Article  CAS  PubMed  Google Scholar 

  28. Matus, A., De Petris, S. & Raff, M. C. Mobility of concanavalin A receptors in myelin and synaptic membranes. Nature New Biol. 244, 278–280 (1973).

    Article  CAS  PubMed  Google Scholar 

  29. Clark, R. A. et al. Identification of lectin-purified neural glycoproteins, GPs 180, 116, and 110, with NMDA and AMPA receptor subunits: conservation of glycosylation at the synapse. J. Neurochem. 70, 2594–2605 (1998).

    Article  CAS  PubMed  Google Scholar 

  30. Villanueva, S. & Steward, O. Glycoprotein synthesis at the synapse: fractionation of polypeptides synthesized within isolated dendritic fragments by concanavalin A affinity chromatography. Brain Res. Mol. Brain Res. 91, 137–147 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. Dotti, C. G. & Simons, K. Polarized sorting of viral glycoproteins to the axon and dendrites of hippocampal neurons in culture. Cell 62, 63–72 (1990).

    Article  CAS  PubMed  Google Scholar 

  32. Gloor, S. et al. The adhesion molecule on glia (AMOG) is a homologue of the beta subunit of the Na,K-ATPase. J. Cell Biol. 110, 165–174 (1990).

    Article  CAS  PubMed  Google Scholar 

  33. Horstkorte, R., Schachner, M., Magyar, J. P., Vorherr, T. & Schmitz, B. The fourth immunoglobulin-like domain of NCAM contains a carbohydrate recognition domain for oligomannosidic glycans implicated in association with L1 and neurite outgrowth. J. Cell Biol. 121, 1409–1421 (1993). This study provides the first evidence of a functional cis -interaction between adhesion molecules mediated by a glycan (see also references 39 and 48).

    Article  CAS  PubMed  Google Scholar 

  34. Simon, H., Klinz, S., Fahrig, T. & Schachner, M. Molecular association of the neural adhesion molecules L1 and N-CAM in the surface membrane of neuroblastoma cells is shown by chemical cross-linking. Eur. J. Neurosci. 3, 634–640 (1991).

    Article  PubMed  Google Scholar 

  35. Thor, G., Pollerberg, E. G. & Schachner, M. Molecular association of two neural cell adhesion molecules within the surface membrane of cultured mouse neuroblastoma cells. Neurosci. Lett. 66, 121–126 (1986).

    Article  CAS  PubMed  Google Scholar 

  36. Heiland, P. C. et al. Tyrosine and serine phosphorylation of the neural cell adhesion molecule L1 is implicated in its oligomannosidic glycan dependent association with NCAM and neurite outgrowth. Eur. J. Cell Biol. 75, 97–106 (1998).

    Article  CAS  PubMed  Google Scholar 

  37. Luthi, A., Laurent, J. P., Figurov, A., Muller, D. & Schachner, M. Hippocampal long-term potentiation and neural cell adhesion molecules L1 and NCAM. Nature 372, 777–779 (1994).

    Article  PubMed  Google Scholar 

  38. Doherty, P. & Walsh, F. S. Cell adhesion molecules, second messengers and axonal growth. Curr. Opin. Neurobiol. 2, 595–601 (1992).

    Article  CAS  PubMed  Google Scholar 

  39. Heller, M., von der Ohe, M., Kleene, R., Mohajeri, M. H. & Schachner, M. The immunoglobulin-superfamily molecule basigin is a binding protein for oligomannosidic carbohydrates: an anti-idiotypic approach. J. Neurochem. 84, 557–565 (2003). Description of an unconventional approach to identify receptors for glycans.

    Article  CAS  PubMed  Google Scholar 

  40. Crocker, P. R. Siglecs: sialic-acid-binding immunoglobulin-like lectins in cell–cell interactions and signalling. Curr. Opin. Struct. Biol. 12, 609–615 (2002).

    Article  CAS  PubMed  Google Scholar 

  41. Tang, S. et al. Myelin-associated glycoprotein interacts with neurons via a sialic acid binding site at Arg118 and a distinct neurite inhibition site. J. Cell Biol. 138, 1355–1366 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Schachner, M. & Bartsch, U. Multiple functions of the myelin-associated glycoprotein MAG (siglec-4a) in formation and maintenance of myelin. Glia 29, 154–165 (2000).

    Article  CAS  PubMed  Google Scholar 

  43. Bartsch, U. et al. Lack of evidence that myelin-associated glycoprotein is a major inhibitor of axonal regeneration in the CNS. Neuron 15, 1375–1381 (1995).

    Article  CAS  PubMed  Google Scholar 

  44. Filbin, M. T. Myelin-associated glycoprotein: a role in myelination and in the inhibition of axonal regeneration? Curr. Opin. Neurobiol. 5, 588–595 (1995).

    Article  CAS  PubMed  Google Scholar 

  45. Vyas, A. A. et al. Gangliosides are functional nerve cell ligands for myelin-associated glycoprotein (MAG), an inhibitor of nerve regeneration. Proc. Natl Acad. Sci. USA 99, 8412–8417 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Vyas, A. A. & Schnaar, R. L. Brain gangliosides: functional ligands for myelin stability and the control of nerve regeneration. Biochimie 83, 677–682 (2001).

    Article  CAS  PubMed  Google Scholar 

  47. O'Leary, C. P. & Willison, H. J. Autoimmune ataxic neuropathies (sensory ganglioneuropathies). Curr. Opin. Neurol. 10, 366–370 (1997).

    Article  CAS  PubMed  Google Scholar 

  48. Kleene, R., Yang, H., Kutsche, M. & Schachner, M. The neural recognition molecule L1 is a sialic acid-binding lectin for CD24, which induces promotion and inhibition of neurite outgrowth. J. Biol. Chem. 276, 21656–21663 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. Du, Y. Z., Srivastava, A. K. & Schwartz, C. E. Multiple exon screening using restriction endonuclease fingerprinting (REF): detection of six novel mutations in the L1 cell adhesion molecule (L1CAM) gene. Hum. Mutat. 11, 222–230 (1998).

    Article  CAS  PubMed  Google Scholar 

  50. Finckh, U. et al. Spectrum and detection rate of L1CAM mutations in isolated and familial cases with clinically suspected L1-disease. Am. J. Med. Genet. 92, 40–46 (2000).

    Article  CAS  PubMed  Google Scholar 

  51. Hardelin, J. P. et al. Heterogeneity in the mutations responsible for X-chromosome-linked Kallmann syndrome. Hum. Mol. Genet. 2, 373–377 (1993).

    Article  CAS  PubMed  Google Scholar 

  52. Holm, J. et al. Structural features of a close homologue of L1 (CHL1) in the mouse: a new member of the L1 family of neural recognition molecules. Eur. J. Neurosci. 8, 1613–1629 (1996).

    Article  CAS  PubMed  Google Scholar 

  53. Maeda, Y. et al. Induction of demyelination by intraneural injection of antibodies against sulfoglucuronyl paragloboside. Exp. Neurol. 113, 221–225 (1991).

    Article  CAS  PubMed  Google Scholar 

  54. Gallego, R. G. et al. Epitope diversity of N-glycans from bovine peripheral myelin glycoprotein P0 revealed by mass spectrometry and nano probe magic angle spinning 1H NMR spectroscopy. J. Biol. Chem. 276, 30834–30844 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. Yuen, C. T. et al. Brain contains HNK-1 immunoreactive O-glycans of the sulfoglucuronyl lactosamine series that terminate in 2-linked or 2,6-linked hexose (mannose). J. Biol. Chem. 272, 8924–8931 (1997).

    Article  CAS  PubMed  Google Scholar 

  56. Schachner, M. & Martini, R. Glycans and the modulation of neural-recognition molecule function. Trends Neurosci. 18, 183–191 (1995).

    Article  CAS  PubMed  Google Scholar 

  57. Vogel, M., Zimmermann, H. & Singer, W. Transient association of the HNK-1 epitope with 5′-nucleotidase during development of the cat visual cortex. Eur. J. Neurosci. 5, 1423–1425 (1993).

    Article  CAS  PubMed  Google Scholar 

  58. Hall, H., Carbonetto, S. & Schachner, M. L1/HNK-1 carbohydrate- and β1 integrin-dependent neural cell adhesion to laminin-1. J. Neurochem. 68, 544–553 (1997).

    Article  CAS  PubMed  Google Scholar 

  59. Margolis, R. K., Ripellino, J. A., Goossen, B., Steinbrich, R. & Margolis, R. U. Occurrence of the HNK-1 epitope (3-sulfoglucuronic acid) in PC12 pheochromocytoma cells, chromaffin granule membranes, and chondroitin sulfate proteoglycans. Biochem. Biophys. Res. Commun. 145, 1142–1148 (1987).

    Article  CAS  PubMed  Google Scholar 

  60. Chou, D. K., Evans, J. E. & Jungalwala, F. B. Identity of nuclear high-mobility-group protein, HMG-1, and in brain. J. Neurochem. 77, 120–131 (2001).

    Article  CAS  PubMed  Google Scholar 

  61. Hall, H., Vorherr, T. & Schachner, M. Characterization of a 21 amino acid peptide sequence of the laminin G2 domain that is involved in HNK-1 carbohydrate binding and cell adhesion. Glycobiology 5, 435–441 (1995).

    Article  CAS  PubMed  Google Scholar 

  62. Hall, H. et al. HNK-1 carbohydrate-mediated cell adhesion to laminin-1 is different from heparin-mediated and sulfatide-mediated cell adhesion. Eur. J. Biochem. 246, 233–242 (1997).

    Article  CAS  PubMed  Google Scholar 

  63. Miura, R., Ethell, I. M. & Yamaguchi, Y. Carbohydrate-protein interactions between HNK-1-reactive sulfoglucuronyl glycolipids and the proteoglycan lectin domain mediate neuronal cell adhesion and neurite outgrowth. J. Neurochem. 76, 413–424 (2001). An important contribution to the function of the HNK1 glycan in proteoglycan-mediated neuronal interactions.

    Article  CAS  PubMed  Google Scholar 

  64. Miura, R. et al. The proteoglycan lectin domain binds sulfated cell surface glycolipids and promotes cell adhesion. J. Biol. Chem. 274, 11431–11438 (1999).

    Article  CAS  PubMed  Google Scholar 

  65. Griffith, L. S., Schmitz, B. & Schachner, M. L2/HNK-1 carbohydrate and protein-protein interactions mediate the homophilic binding of the neural adhesion molecule P0. J. Neurosci. Res. 33, 639–648 (1992).

    Article  CAS  PubMed  Google Scholar 

  66. Cole, G. J. & Schachner, M. Localization of the L2 monoclonal antibody binding site on chicken neural cell adhesion molecule (NCAM) and evidence for its role in NCAM-mediated cell adhesion. Neurosci. Lett. 78, 227–232 (1987).

    Article  CAS  PubMed  Google Scholar 

  67. Kallapur, S. G. & Akeson, R. A. The neural cell adhesion molecule (NCAM) heparin binding domain binds to cell surface heparan sulfate proteoglycans. J. Neurosci. Res. 33, 538–548 (1992).

    Article  CAS  PubMed  Google Scholar 

  68. Martini, R., Schachner, M. & Brushart, T. M. The L2/HNK-1 carbohydrate is preferentially expressed by previously motor axon-associated Schwann cells in reinnervated peripheral nerves. J. Neurosci. 14, 7180–7191 (1994). A study on the complex regulation of HNK1 expression in peripheral nervous system regeneration.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Low, K., Orberger, G., Schmitz, B., Martini, R. & Schachner, M. The L2/HNK-1 carbohydrate is carried by the myelin associated glycoprotein and sulphated glucuronyl glycolipids in muscle but not cutaneous nerves of adult mice. Eur. J. Neurosci. 6, 1773–1781 (1994).

    Article  CAS  PubMed  Google Scholar 

  70. Simon-Haldi, M., Mantei, N., Franke, J., Voshol, H. & Schachner, M. Identification of a peptide mimic of the L2/HNK-1 carbohydrate epitope. J. Neurochem. 83, 1380–1388 (2002). This study provides a basis for the identification of peptide mimics for the functions of the HNK1 glycan.

    Article  CAS  PubMed  Google Scholar 

  71. Strekalova, T., Wotjak, C. T. & Schachner, M. Intrahippocampal administration of an antibody against the HNK-1 carbohydrate impairs memory consolidation in an inhibitory learning task in mice. Mol. Cell. Neurosci. 17, 1102–1113 (2001).

    Article  CAS  PubMed  Google Scholar 

  72. Pradel, G., Schachner, M. & Schmidt, R. Inhibition of memory consolidation by antibodies against cell adhesion molecules after active avoidance conditioning in zebrafish. J. Neurobiol. 39, 197–206 (1999).

    Article  CAS  PubMed  Google Scholar 

  73. Senn, C. et al. Mice deficient for the HNK-1 sulfotransferase show alterations in synaptic efficacy and spatial learning and memory. Mol. Cell. Neurosci. 20, 712–729 (2002).

    Article  CAS  PubMed  Google Scholar 

  74. Yamamoto, S. et al. Mice deficient in nervous system-specific carbohydrate epitope HNK-1 exhibit impaired synaptic plasticity and spatial learning. J. Biol. Chem. 277, 27227–27231 (2002).

    Article  CAS  PubMed  Google Scholar 

  75. Saghatelyan, A. K. et al. The extracellular matrix molecule tenascin-R and its HNK-1 carbohydrate modulate perisomatic inhibition and long-term potentiation in the CA1 region of the hippocampus. Eur. J. Neurosci. 12, 3331–3342 (2000).

    Article  CAS  PubMed  Google Scholar 

  76. Dityatev, A. & Schachner, M. Extracellular matrix molecules and synaptic plasticity. Nature Rev. Neurosci. 4, 456–468 (2003). Review on the interaction of the HNK1 carbohydrate with the metabotropic GABA receptor that leads to a complex set of functional consequences in inhibitory synapses in the hippocampus.

    Article  CAS  Google Scholar 

  77. Casu, B. & Lindahl, U. Structure and biological interactions of heparin and heparan sulfate. Adv. Carbohydr. Chem. Biochem. 57, 159–206 (2001). A recent account of structure–function relationships of sulphate groups in glycosaminoglycans.

    Article  CAS  PubMed  Google Scholar 

  78. Yamaguchi, Y. Lecticans: organizers of the brain extracellular matrix. Cell. Mol. Life Sci. 57, 276–289 (2000). A comprehensive review on an interesting family of extracellular matrix proteoglycans.

    Article  CAS  PubMed  Google Scholar 

  79. Bruckner, G. et al. Postnatal development of perineuronal nets in wild-type mice and in a mutant deficient in tenascin-R. J. Comp. Neurol. 428, 616–629 (2000).

    Article  CAS  PubMed  Google Scholar 

  80. Kalb, R. G. & Hockfield, S. Induction of a neuronal proteoglycan by the NMDA receptor in the developing spinal cord. Science 250, 294–296 (1990).

    Article  CAS  PubMed  Google Scholar 

  81. Kaksonen, M. et al. Syndecan-3-deficient mice exhibit enhanced LTP and impaired hippocampus-dependent memory. Mol. Cell. Neurosci. 21, 158–172 (2002).

    Article  CAS  PubMed  Google Scholar 

  82. Jenniskens, G. J., Oosterhof, A., Brandwijk, R., Veerkamp, J. H. & van Kuppevelt, T. H. Heparan sulfate heterogeneity in skeletal muscle basal lamina: demonstration by phage display-derived antibodies. J. Neurosci. 20, 4099–4111 (2000). A new approach to identify structural differences in heparan sulphates by phage displayed antibodies.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Bukalo, O., Schachner, M. & Dityatev, A. Modification of extracellular matrix by enzymatic removal of chondroitin sulfate and by lack of tenascin-R differentially affects several forms of synaptic plasticity in the hippocampus. Neuroscience 104, 359–369 (2001).

    Article  CAS  PubMed  Google Scholar 

  84. Brakebusch, C. et al. Brevican-deficient mice display impaired hippocampal CA1 long-term potentiation but show no obvious deficits in learning and memory. Mol. Cell. Biol. 22, 7417–7427 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Zhou, X. H. et al. Neurocan is dispensable for brain development. Mol. Cell. Biol. 21, 5970–5978 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Becker, C. G. & Becker, T. Repellent guidance of regenerating optic axons by chondroitin sulfate glycosaminoglycans in zebrafish. J. Neurosci. 22, 842–853 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Asher, R. A., Morgenstern, D. A., Moon, L. D. & Fawcett, J. W. Chondroitin sulphate proteoglycans: inhibitory components of the glial scar. Prog. Brain Res. 132, 611–619 (2001).

    Article  CAS  PubMed  Google Scholar 

  88. Grimpe, B. & Silver, J. The extracellular matrix in axon regeneration. Prog. Brain Res. 137, 333–349 (2002). A review on the seminal identification of the functional importance of chondroitin sulphate in vitro.

    Article  CAS  PubMed  Google Scholar 

  89. Bradbury, E. J. et al. Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature 416, 636–640 (2002). An in vivo follow-up on the prediction that removal of chondroitin sulphate allows axon regrowth in the central nervous system.

    Article  CAS  PubMed  Google Scholar 

  90. Pizzorusso, T. et al. Reactivation of ocular dominance plasticity in the adult visual cortex. Science 298, 1248–1251 (2002). An important study on the role of chondroitin sulphate as a regulator of synaptic plasticity.

    Article  CAS  PubMed  Google Scholar 

  91. Chen, Y. J. et al. Neutral N-glycans in adult rat brain tissue — complete characterisation reveals fucosylated hybrid and complex structures. Eur. J. Biochem. 251, 691–703 (1998).

    Article  CAS  PubMed  Google Scholar 

  92. Zamze, S. et al. Sialylated N-glycans in adult rat brain tissue — a widespread distribution of disialylated antennae in complex and hybrid structures. Eur. J. Biochem. 258, 243–270 (1998).

    Article  CAS  PubMed  Google Scholar 

  93. Chai, W. et al. High prevalence of 2-mono- and 2,6-di-substituted manol-terminating sequences among O-glycans released from brain glycopeptides by reductive alkaline hydrolysis. Eur. J. Biochem. 263, 879–888 (1999).

    Article  CAS  PubMed  Google Scholar 

  94. Smalheiser, N. R., Haslam, S. M., Sutton-Smith, M., Morris, H. R. & Dell, A. Structural analysis of sequences O-linked to mannose reveals a novel Lewisx structure in cranin (dystroglycan) purified from sheep brain. J. Biol. Chem. 273, 23698–23703 (1998).

    Article  CAS  PubMed  Google Scholar 

  95. Chiba, A. et al. Structures of sialylated O-linked oligosaccharides of bovine peripheral nerve α-dystroglycan. The role of a novel O-mannosyl-type oligosaccharide in the binding of α-dystroglycan with laminin. J. Biol. Chem. 272, 2156–2162 (1997).

    Article  CAS  PubMed  Google Scholar 

  96. Wing, D. R., Rademacher, T. W., Schmitz, B., Schachner, M. & Dwek, R. A. Comparative glycosylation in neural adhesion molecules. Biochem. Soc. Trans. 20, 386–390 (1992).

    Article  CAS  PubMed  Google Scholar 

  97. Akita, K. et al. Identification of the core protein carrying the Tn antigen in mouse brain: specific expression on syndecan-3. Cell. Struct. Funct. 26, 271–278 (2001).

    Article  CAS  PubMed  Google Scholar 

  98. Ojima, H., Sakai, M. & Ohyama, J. Molecular heterogeneity of Vicia villosa-recognized perineuronal nets surrounding pyramidal and nonpyramidal neurons in the guinea pig cerebral cortex. Brain Res. 786, 274–280 (1998).

    Article  CAS  PubMed  Google Scholar 

  99. Apostolski, S. et al. Identification of Galβ(1-3)GalNAc bearing glycoproteins at the nodes of Ranvier in peripheral nerve. J. Neurosci. Res. 38, 134–141 (1994).

    Article  CAS  PubMed  Google Scholar 

  100. Thomas, F. P. Antibodies to GM1 and Galβ(1-3)GalNAc at the nodes of Ranvier in human and experimental autoimmune neuropathy. Microsc. Res. Tech. 34, 536–543 (1996).

    Article  CAS  PubMed  Google Scholar 

  101. Cooper, D. N. & Barondes, S. H. God must love galectins; he made so many of them. Glycobiology 9, 979–984 (1999).

    Article  CAS  PubMed  Google Scholar 

  102. Pesheva, P., Kuklinski, S., Schmitz, B. & Probstmeier, R. Galectin-3 promotes neural cell adhesion and neurite growth. J. Neurosci. Res. 54, 639–654 (1998).

    Article  CAS  PubMed  Google Scholar 

  103. Parkhomovskiy, N., Kammesheidt, A. & Martin, P. T. N-acetyllactosamine and the CT carbohydrate antigen mediate agrin-dependent activation of MuSK and acetylcholine receptor clustering in skeletal muscle. Mol. Cell. Neurosci. 15, 380–397 (2000).

    Article  CAS  PubMed  Google Scholar 

  104. Sasaki, T. & Endo, T. Both cell-surface carbohydrates and protein tyrosine phosphatase are involved in the differentiation of astrocytes in vitro. Glia 32, 60–70 (2000).

    Article  CAS  PubMed  Google Scholar 

  105. Sasaki, T. & Endo, T. Evidence for the presence of N-CAM 180 on astrocytes from rat cerebellum and differences in glycan structures between N-CAM 120 and N-CAM 140. Glia 28, 236–243 (1999).

    Article  CAS  PubMed  Google Scholar 

  106. Dowsing, B., Puche, A., Hearn, C. & Key, B. Presence of novel N-CAM glycoforms in the rat olfactory system. J. Neurobiol. 32, 659–670 (1997).

    Article  CAS  PubMed  Google Scholar 

  107. Key, B. & Anderson, R. B. Neuronal pathfinding during development of the rostral brain in Xenopus. Clin. Exp. Pharmacol. Physiol. 26, 752–754 (1999).

    Article  CAS  PubMed  Google Scholar 

  108. Pays, L. & Schwarting, G. Gal-NCAM is a differentially expressed marker for mature sensory neurons in the rat olfactory system. J. Neurobiol. 43, 173–185 (2000).

    Article  CAS  PubMed  Google Scholar 

  109. Smalla, K. H., Angenstein, F., Richter, K., Gundelfinger, E. D. & Staak, S. Identification of fucose α(1-2) galactose epitope-containing glycoproteins from rat hippocampus. Neuroreport 9, 813–817 (1998).

    Article  CAS  PubMed  Google Scholar 

  110. Gocht, A., Struckhoff, G. & Lohler, J. CD15-containing glycoconjugates in the central nervous system. Histol. Histopathol. 11, 1007–1028 (1996).

    CAS  PubMed  Google Scholar 

  111. Capela, A. & Temple, S. LeX/SSEA-1 is expressed by adult mouse CNS stem cells, identifying them as nonependymal. Neuron 35, 865–875 (2002).

    Article  PubMed  Google Scholar 

  112. Sajdel-Sulkowska, E. M. Immunofluorescent detection of CD15-fucosylated glycoconjugates in primary cerebellar cultures and their function in glial-neuronal adhesion in the central nervous system. Acta Biochim. Pol. 45, 781–790 (1998).

    CAS  PubMed  Google Scholar 

  113. Marquardt, T. & Denecke, J. Congenital disorders of glycosylation: review of their molecular bases, clinical presentations and specific therapies. Eur. J. Pediatr. 162, 359–379 (2003). A comprehensive review on the genetic and clinical aspects of glycosylation disorders.

    CAS  PubMed  Google Scholar 

  114. Low, J. B. & Marth, J. D. A genetic approach to mammalian glycan function. Annu. Rev. Biochem. 72, 643–691 (2003). A scholarly compilation of the functional consequences of glycosyltransferase deficiencies.

    Article  CAS  Google Scholar 

  115. Yoshida, A. et al. Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltransferase, POMGnT1. Dev. Cell. 1, 717–724 (2001).

    Article  CAS  PubMed  Google Scholar 

  116. Beltran-Valero de Bernabe, D. et al. Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome. Am. J. Hum. Genet. 71, 1033–1043 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Shi, S. & Stanley, P. Protein O-fucosyltransferase 1 is an essential component of Notch signaling pathways. Proc. Natl Acad. Sci. USA 100, 5234–5239 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Givogri, M. I. et al. Central nervous system myelination in mice with deficient expression of Notch1 receptor. J. Neurosci. Res. 67, 309–320 (2002).

    Article  CAS  PubMed  Google Scholar 

  119. Stump, G. et al. Notch1 and its ligands Delta-like and Jagged are expressed and active in distinct cell populations in the postnatal mouse brain. Mech. Dev. 114, 153–159 (2002).

    Article  CAS  PubMed  Google Scholar 

  120. Ishii, Y., Nakamura, S. & Osumi, N. Demarcation of early mammalian cortical development by differential expression of fringe genes. Brain Res. Dev. Brain Res. 119, 307–320 (2000).

    Article  CAS  PubMed  Google Scholar 

  121. Haltiwanger, R. S. & Stanley, P. Modulation of receptor signaling by glycosylation: fringe is an O-fucose-β1,3-N-acetylglucosaminyltransferase. Biochim. Biophys. Acta. 1573, 328–335 (2002). Review on a genetically identified glycosyltransferase that impinges on the fascinating notch signalling pathway.

    Article  CAS  PubMed  Google Scholar 

  122. Martin, P. T. Glycobiology of the synapse. Glycobiology 12, 1R–7R (2002). A timely account on the importance of glycans at the neuromuscular junction.

    Article  CAS  PubMed  Google Scholar 

  123. Vutskits, L. et al. PSA-NCAM modulates BDNF-dependent survival and differentiation of cortical neurons. Eur. J. Neurosci. 13, 1391–1402 (2001).

    Article  CAS  PubMed  Google Scholar 

  124. Muller, D. et al. Brain-derived neurotrophic factor restores long-term potentiation in polysialic acid-neural cell adhesion molecule-deficient hippocampus. Proc. Natl Acad. Sci. USA 97, 4315–4320 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Joliot, A. H., Triller, A., Volovitch, M., Pernelle, C. & Prochiantz, A. α-2,8-Polysialic acid is the neuronal surface receptor of antennapedia homeobox peptide. New Biol. 3, 1121–1134 (1991).

    CAS  PubMed  Google Scholar 

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Acknowledgements

The authors are grateful to A. Dityatev for his comments on the manuscript and the Deutsche Forschungsgemeinschaft for support.

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Authors and Affiliations

  1. Zentrum für Molekulare Neurobiologie, Universität Hamburg, Martinistrasse 52, Hamburg, 20246, Germany

    Ralf Kleene & Melitta Schachner

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  1. Ralf Kleene
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Correspondence to Melitta Schachner.

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DATABASES

LocusLink

agrin

AMOG

brevican

CD24

CHL1

DCC

DSCAM

F3/F11/contactin

L1

MAG

NCAM

neogenin

neurofascin

neuroglian

perlecan

sidekick

TAG1/TAX1/axonin

telencephalin

tenascin-R

Swiss-Prot

NgCAM

NrCAM

Glossary

GLYCOSIDIC BONDS

Covalent bonds that are formed between two monosaccharide molecules by means of a dehydration reaction. The linkage terminology is based on which carbon atoms in the two sugars are linked and the position of the linking oxygen group. For example, if carbon-1 (C-1) of sugar-1 is linked to C-4 of sugar-2, and the linking oxygen is below the plane of the sugar-1 ring, the linkage is referred to as an α1,4 glycosidic bond. If the oxygen had been above the plane of the ring, the linkage would be designated β1,4.

MUCIN

A highly glycosylated protein that is rich in serine and/or threonine O-glycosylation.

ROSTRAL MIGRATORY STREAM

Neuroblasts from the subventricular zone migrate in the rostral migratory stream (RMS) towards the olfactory bulb in a so-called tangential migration and move from the rostral tip of the migratory stream by detaching from each other to initiate radial migration to their target areas in the olfactory bulb.

MOSSY FIBRES

Axons of dentate gyrus granule cells, which constitute the main excitatory input to CA3 pyramidal cells in the hippocampus.

PERFORATED SYNAPSES

Synapses in which the postsynaptic density is discontinuous.

VOLUME TRANSMISSION

A mechanism of extrasynaptic intercellular communication that relies on signal diffusion through the extracellular fluid.

RECOGNITION MOLECULE

Recognition molecules belong to diverse sets of families, such as the immunoglobulin superfamily, the integrin family, the receptor tyrosine kinase families, and epidermal growth factor repeats-containing family of molecules. Glycolipids and proteoglycans are also recognition molecules. As carbohydrate-carrying proteins, they can be either transmembrane molecules, glycosylphosphatidyl inositol anchored to the cell surface or extracellular matrix molecules that fill the space between cells.

EPITOPE

Part of a molecule that is recognized by an antibody. It consists of several monosaccharides and/or amino acids, and in the case of a glycan it can be exposed in a distinct three-dimensional configuration, often in particular arrangements with amino acids.

HIGH-MOBILITY GROUP PROTEINS

Non-histone proteins that are involved in chromatin structure and gene regulation.

PEPTIDOMIMETICS

Peptidomimetics are peptides that mimic other molecules, for example, carbohydrates, in their ability to bind to other molecules. In terms of three-dimensional structure, they are similar to the compounds that they mimic.

STEP-DOWN PASSIVE AVOIDANCE TASK

A behavioural experiment, in which an animal learns to associate stepping down from a raised platform with an aversive stimulus, such as electric shock. The name of the task derives from the fact that the animal learns to passively stay on the platform to avoid the stimulus.

INWARDLY RECTIFYING K+ CHANNELS

Potassium channels that allow long depolarizing responses, as they close during depolarizing pulses and open with steep voltage dependence on hyperpolarization. They are called inward rectifiers because current flows through them more easily into than out of the cell.

PERINEURONAL NETS

Agglomerates of extracellular matrix components, including molecules of the lectican family of chondroitin sulphate proteoglycans, such as aggrecan, versican, brevican and neurocan, as well as hyaluronan and tenascin-R or tenascin-C. These accumulations are found around cell bodies and dendrites of certain classes of neurons, mainly parvalbumin-positive inhibitory interneurons. The function of these nets is unknown, but probably relates to the regulation of synaptic plasticity.

AMBLYOPIC

Amblyopia is an eye problem that causes poor vision. It is also known as 'lazy eye', and is often associated with squint.

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Kleene, R., Schachner, M. Glycans and neural cell interactions. Nat Rev Neurosci 5, 195–208 (2004). https://doi.org/10.1038/nrn1349

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