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The dual role of the extracellular matrix in synaptic plasticity and homeostasis

Key Points

  • Several extracellular matrix (ECM) components, such as Reelin, integrin ligands, tenascin C and hyaluronic acid, regulate induction of synaptic plasticity through their modulatory effects on NMDA (N-methyl-D-aspartate) receptors and L-type voltage-dependent Ca2+ channels, which are the major players in triggering activity-dependent synaptic changes.

  • Following induction of long-term potentiation (LTP), stabilization of new synaptic configurations requires integrin signalling through the Src family of tyrosine kinases, which contributes to the regulation of the localization and activity of small GTPases that coordinate actin cytoskeleton remodelling and stabilization.

  • β3 integrins and neuronal pentraxins regulate homeostatic scaling of excitatory postsynaptic currents on excitatory and inhibitory neurons, respectively, through control of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor trafficking and aggregation. Tenascin R is important for metaplastic adjustment of the threshold for induction of LTP in area CA1 of the hippocampus, where it regulates perisomatic innervation of pyramidal neurons.

  • Stabilization of functional microcircuits at the end of the 'critical period' in brain development is thought to involve formation of the chondroitin sulphate-rich ECM that serves as an inhibitory 'barrier' to restrain structural plasticity in the visual cortex and enable formation of erasure-resistant emotional memories in the amygdala.

  • Activity-dependent proteolytic cleavage of ECM components regulates various forms of synaptic plasticity. Proteolytic activity of matrix metalloproteinase 9 promotes hippocampal LTP through the activation of integrin-dependent signalling. Integrin activation is mediated by proteolytic unmasking of a cryptic Arg-Gly-Asp motif of a not yet identified ECM component.

  • The proteolytic function of the synaptic serine protease neurotrypsin is activated in an NMDA receptor-dependent manner when a presynaptic and a postsynaptic neuron fire together. Cleavage of agrin by neurotrypsin unmasks a previously unaccessible filopodia-promoting site on the released carboxy-terminal 22-kDa fragment (agrin 22). Activity-dependent generation of dendritic filopodia by released agrin 22 is thought to contribute to activity-dependent synaptogenesis and reorganization of neural circuits.

Abstract

Recent studies have deepened our understanding of multiple mechanisms by which extracellular matrix (ECM) molecules regulate various aspects of synaptic plasticity and have strengthened a link between the ECM and learning and memory. New findings also support the view that the ECM is important for homeostatic processes, such as scaling of synaptic responses, metaplasticity and stabilization of synaptic connectivity. Activity-dependent modification of the ECM affects the formation of dendritic filopodia and the growth of dendritic spines. Thus, the ECM has a dual role as a promoter of structural and functional plasticity and as a degradable stabilizer of neural microcircuits. Both of these aspects are likely to be important for mental health.

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Figure 1: Role of the ECM in induction of synaptic plasticity.
Figure 2: NMDA receptor and integrin co-signalling regulates cytoskeletal dynamics during stabilization of long-term potentiation.
Figure 3: Role of the ECM in homeostatic plasticity.
Figure 4: Proteolytic unmasking of ECM-resident signalling functions.

References

  1. Dityatev, A. & Schachner, M. Extracellular matrix molecules and synaptic plasticity. Nature Rev. Neurosci. 4, 456–468 (2003).

    Article  CAS  Google Scholar 

  2. Malenka, R. C. & Nicoll, R. A. Long-term potentiation — a decade of progress? Science 285, 1870–1874 (1999).

    Article  CAS  PubMed  Google Scholar 

  3. Huber, K. M., Mauk, M. D. & Kelly, P. T. Distinct LTP induction mechanisms: contribution of NMDA receptors and voltage-dependent calcium channels. J. Neurophysiol. 73, 270–279 (1995).

    Article  CAS  PubMed  Google Scholar 

  4. Herz, J. & Chen, Y. Reelin, lipoprotein receptors and synaptic plasticity. Nature Rev. Neurosci. 7, 850–859 (2006).

    Article  CAS  Google Scholar 

  5. Tissir, F. & Goffinet, A. M. Reelin and brain development. Nature Rev. Neurosci. 4, 496–505 (2003).

    Article  CAS  Google Scholar 

  6. Frotscher, M. Role for Reelin in stabilizing cortical architecture. Trends Neurosci. 33, 407–414 (2010).

    Article  CAS  PubMed  Google Scholar 

  7. Beffert, U. et al. Functional dissection of Reelin signaling by site-directed disruption of Disabled-1 adaptor binding to apolipoprotein E receptor 2: distinct roles in development and synaptic plasticity. J. Neurosci. 26, 2041–2052 (2006). This elegant study reveals the importance of a specific domain of the lipoprotein receptor APOER2 in Reelin signalling through NMDA receptors.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Weeber, E. J. et al. Reelin and ApoE receptors cooperate to enhance hippocampal synaptic plasticity and learning. J. Biol. Chem. 277, 39944–39952 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Qiu, S., Zhao, L. F., Korwek, K. M. & Weeber, E. J. Differential reelin-induced enhancement of NMDA and AMPA receptor activity in the adult hippocampus. J. Neurosci. 26, 12943–12955 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Beffert, U. et al. Modulation of synaptic plasticity and memory by Reelin involves differential splicing of the lipoprotein receptor Apoer2. Neuron 47, 567–579 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Lang, U. E., Puls, I., Muller, D. J., Strutz-Seebohm, N. & Gallinat, J. Molecular mechanisms of schizophrenia. Cell. Physiol. Biochem. 20, 687–702 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Wedenoja, J. et al. Replication of linkage on chromosome 7q22 and association of the regional Reelin gene with working memory in schizophrenia families. Mol. Psychiatry 13, 673–684 (2008).

    Article  CAS  PubMed  Google Scholar 

  13. Qiu, S. et al. Cognitive disruption and altered hippocampus synaptic function in Reelin haploinsufficient mice. Neurobiol. Learn. Mem. 85, 228–242 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Barr, A. M., Fish., K. N., Markou, A. & Honer, W. G. Heterozygous reeler mice exhibit alterations in sensorimotor gating but not presynaptic proteins. Eur. J. Neurosci. 27, 2568–2574 (2008).

    Article  PubMed  Google Scholar 

  15. Brigman, J. L., Padukiewicz, K. E., Sutherland, M. L. & Rothblat, L. A. Executive functions in the heterozygous reeler mouse model of schizophrenia. Behav. Neurosci. 120, 984–988 (2006).

    Article  PubMed  Google Scholar 

  16. Pujadas, L. et al. Reelin regulates postnatal neurogenesis and enhances spine hypertrophy and long-term potentiation. J. Neurosci. 30, 4636–4649 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Durakoglugil, M. S., Chen, Y., White, C. L., Kavalali, E. T. & Herz, J. Reelin signaling antagonizes β-amyloid at the synapse. Proc. Natl Acad. Sci. USA 106, 15938–15943 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Bernard-Trifilo, J. A. et al. Integrin signaling cascades are operational in adult hippocampal synapses and modulate NMDA receptor physiology. J. Neurochem. 93, 834–849 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Cingolani, L. A. et al. Activity-dependent regulation of synaptic AMPA receptor composition and abundance by β3 integrins. Neuron 58, 749–762 (2008). This work dissects the signalling mechanisms by which β3 integrins regulate synaptic scaling in cultured hippocampal neurons.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Evers, M. R. et al. Impairment of L-type Ca2+ channel-dependent forms of hippocampal synaptic plasticity in mice deficient in the extracellular matrix glycoprotein tenascin-C. J. Neurosci. 22, 7177–7194 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Strekalova, T. et al. Fibronectin domains of extracellular matrix molecule tenascin-C modulate hippocampal learning and synaptic plasticity. Mol. Cell. Neurosci. 21, 173–187 (2002).

    Article  CAS  PubMed  Google Scholar 

  22. Kochlamazashvili, G. et al. The extracellular matrix molecule hyaluronic acid regulates hippocampal synaptic plasticity by modulating postsynaptic L-type Ca2+ channels. Neuron 67, 116–128 (2010). This study combines numerous approaches to demonstrate the role of hyaluronic acid-mediated modulation of Ca v 1.2 channels in LTP and the formation of contextual memories.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lundell, A. et al. Structural basis for interactions between tenascins and lectican C-type lectin domains: evidence for a crosslinking role for tenascins. Structure 12, 1495–1506 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Moosmang, S. et al. Role of hippocampal Cav1.2 Ca2+ channels in NMDA receptor-independent synaptic plasticity and spatial memory. J. Neurosci. 25, 9883–9892 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Pabbidi, M. R., Ji, X., Samarel, A. M. & Lipsius, S. L. Laminin enhances β2-adrenergic receptor stimulation of L-type Ca2+ current via cytosolic phospholipase A2 signalling in cat atrial myocytes. J. Physiol. 587, 4785–4797 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Shi, L., Jian, K., Ko, M. L., Trump, D. & Ko, G. Y. Retinoschisin, a new binding partner for L-type voltage-gated calcium channels in the retina. J. Biol. Chem. 284, 3966–3975 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lacinova, L., Cleemann, L. & Morad, M. Ca2+ channel modulating effects of heparin in mammalian cardiac myocytes. J. Physiol. 465, 181–201 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wu, X. et al. Modulation of calcium current in arteriolar smooth muscle by αvβ3 and α5β1 integrin ligands. J. Cell Biol. 143, 241–252 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Dityatev, A. et al. Activity-dependent formation and functions of chondroitin sulfate-rich extracellular matrix of perineuronal nets. Dev. Neurobiol. 67, 570–588 (2007). This is the first demonstration that removal of the chondroitin sulphate-rich ECM modulates firing of perisomatic interneurons.

    Article  CAS  PubMed  Google Scholar 

  30. Saliba, R. S., Gu, Z., Yan, Z. & Moss, S. J. Blocking L-type voltage-gated Ca2+ channels with dihydropyridines reduces γ-aminobutyric acid type A receptor expression and synaptic inhibition. J. Biol. Chem. 284, 32544–32550 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bramham, C. R. Local protein synthesis, actin dynamics, and LTP consolidation. Curr. Opin. Neurobiol. 18, 524–531 (2008).

    Article  CAS  PubMed  Google Scholar 

  32. Kramar, E. A., Lin, B., Rex, C. S., Gall, C. M. & Lynch, G. Integrin-driven actin polymerization consolidates long-term potentiation. Proc. Natl Acad. Sci. USA 103, 5579–5584 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Rex, C. S. et al. Different Rho GTPase-dependent signaling pathways initiate sequential steps in the consolidation of long-term potentiation. J. Cell Biol. 186, 85–97 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Webb, D. J., Zhang, H., Majumdar, D. & Horwitz, A. F. α5 integrin signaling regulates the formation of spines and synapses in hippocampal neurons. J. Biol. Chem. 282, 6929–6935 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Huveneers, S. & Danen, E. H. Adhesion signaling - crosstalk between integrins, Src and Rho. J. Cell Sci. 122, 1059–1069 (2009).

    Article  CAS  PubMed  Google Scholar 

  36. ten Klooster, J. P., Jaffer, Z. M., Chernoff, J. & Hordijk, P. L. Targeting and activation of Rac1 are mediated by the exchange factor β-Pix. J. Cell Biol. 172, 759–769 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Bass, M. D. et al. p190RhoGAP is the convergence point of adhesion signals from α5β1 integrin and syndecan-4. J. Cell Biol. 181, 1013–1026 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sfakianos, M. K. et al. Inhibition of Rho via Arg and p190RhoGAP in the postnatal mouse hippocampus regulates dendritic spine maturation, synapse and dendrite stability, and behavior. J. Neurosci. 27, 10982–10992 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Chan, C. S. et al. β1-integrins are required for hippocampal AMPA receptor-dependent synaptic transmission, synaptic plasticity, and working memory. J. Neurosci. 26, 223–232 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Huang, Z. et al. Distinct roles of the β1-class integrins at the developing and the mature hippocampal excitatory synapse. J. Neurosci. 26, 11208–11219 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Chun, D., Gall, C. M., Bi, X. & Lynch, G. Evidence that integrins contribute to multiple stages in the consolidation of long term potentiation in rat hippocampus. Neuroscience 105, 815–829 (2001).

    Article  CAS  PubMed  Google Scholar 

  42. Chan, C. S. et al. α3-integrins are required for hippocampal long-term potentiation and working memory. Learn. Mem. 14, 606–615 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Chan, C. S. et al. α8-Integrins are required for hippocampal long-term potentiation but not for hippocampal-dependent learning. Genes Brain Behav. 9, 402–410 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Turrigiano, G. Homeostatic signaling: the positive side of negative feedback. Curr. Opin. Neurobiol. 17, 318–324 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Rich, M. M. & Wenner, P. Sensing and expressing homeostatic synaptic plasticity. Trends Neurosci. 30, 119–125 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Beattie, E. C. et al. Control of synaptic strength by glial TNFα. Science 295, 2282–2285 (2002).

    Article  CAS  PubMed  Google Scholar 

  47. Stellwagen, D. & Malenka, R. C. Synaptic scaling mediated by glial TNF-α. Nature 440, 1054–1059 (2006).

    Article  CAS  PubMed  Google Scholar 

  48. Stornetta, R. L. & Zhu, J. J. Ras and rap signaling in synaptic plasticity and mental disorders. Neuroscientist 29 Apr 2010 (doi:10.1177/1073858410365562).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Chang, M. C. et al. Narp regulates homeostatic scaling of excitatory synapses on parvalbumin-expressing interneurons. Nature Neurosci. 13, 1090–1097 (2010). This study provides in vitro and in vivo evidence that increasing network activity results in a homeostatic increase of excitatory synaptic input onto perisomatic interneurons, which is mediated by the ECM molecule NARP.

    Article  CAS  PubMed  Google Scholar 

  50. Gundelfinger, E. D., Frischknecht, R., Choquet, D. & Heine, M. Converting juvenile into adult plasticity: a role for the brain's extracellular matrix. Eur. J. Neurosci. 31, 2156–2165 (2010).

    Article  PubMed  Google Scholar 

  51. Dityatev, A., Seidenbecher, C. I. & Schachner, M. Compartmentalization from the outside: the extracellular matrix and functional microdomains in the brain. Trends Neurosci. 9 Sep 2010 (doi: 10.1016/j.tins.2010.08.003).

    Article  CAS  PubMed  Google Scholar 

  52. Abraham, W. C. & Bear, M. F. Metaplasticity: the plasticity of synaptic plasticity. Trends Neurosci. 19, 126–130 (1996).

    Article  CAS  PubMed  Google Scholar 

  53. 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 

  54. Saghatelyan, A. K. et al. Recognition molecule associated carbohydrate inhibits postsynaptic GABAB receptors: a mechanism for homeostatic regulation of GABA release in perisomatic synapses. Mol. Cell. Neurosci. 24, 271–282 (2003).

    Article  CAS  PubMed  Google Scholar 

  55. Nikonenko, A., Schmidt, S., Skibo, G., Bruckner, G. & Schachner, M. Tenascin-R-deficient mice show structural alterations of symmetric perisomatic synapses in the CA1 region of the hippocampus. J. Comp. Neurol. 456, 338–349 (2003).

    Article  CAS  PubMed  Google Scholar 

  56. Saghatelyan, A. K. et al. Reduced perisomatic inhibition, increased excitatory transmission, and impaired long-term potentiation in mice deficient for the extracellular matrix glycoprotein tenascin-R. Mol. Cell. Neurosci. 17, 226–240 (2001).

    Article  CAS  PubMed  Google Scholar 

  57. Bukalo, O., Schachner, M. & Dityatev, A. Hippocampal metaplasticity induced by deficiency in the extracellular matrix glycoprotein tenascin-R. J. Neurosci. 27, 6019–6028 (2007). This work provides pharmacological dissection of mechanisms underlying metaplastic changes in the disinhibited CA1 area of the hippocampus in TNR-deficient mice.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Young, J. Z., Isiegas, C., Abel, T. & Nguyen, P. V. Metaplasticity of the late-phase of long-term potentiation: a critical role for protein kinase A in synaptic tagging. Eur. J. Neurosci. 23, 1784–1794 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Thiagarajan, T. C., Lindskog, M. & Tsien, R. W. Adaptation to synaptic inactivity in hippocampal neurons. Neuron 47, 725–737 (2005).

    Article  CAS  PubMed  Google Scholar 

  60. Morellini, F. et al. Improved reversal learning and working memory and enhanced reactivity to novelty in mice with enhanced GABAergic innervation in the dentate gyrus. Cereb. Cortex 1 Mar 2010 (doi: 10.1093/cercor/bhq017).

    Article  PubMed  Google Scholar 

  61. Pizzorusso, T. et al. Reactivation of ocular dominance plasticity in the adult visual cortex. Science 298, 1248–1251 (2002). This study proposed that the chondroitin sulphate-rich ECM in the visual cortex serves as an inhibitory 'barrier' that restrains ocular dominance plasticity.

    Article  CAS  PubMed  Google Scholar 

  62. Pizzorusso, T. et al. Structural and functional recovery from early monocular deprivation in adult rats. Proc. Natl Acad. Sci. USA 103, 8517–8522 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Mataga, N., Mizuguchi, Y. & Hensch, T. K. Experience-dependent pruning of dendritic spines in visual cortex by tissue plasminogen activator. Neuron 44, 1031–1041 (2004).

    Article  CAS  PubMed  Google Scholar 

  64. McGee, A. W., Yang, Y., Fischer, Q. S., Daw, N. W. & Strittmatter, S. M. Experience-driven plasticity of visual cortex limited by myelin and Nogo receptor. Science 309, 2222–2226 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Galtrey, C. M. & Fawcett, J. W. The role of chondroitin sulfate proteoglycans in regeneration and plasticity in the central nervous system. Brain Res. Rev. 54, 1–18 (2007).

    Article  CAS  PubMed  Google Scholar 

  66. Koprivica, V. et al. EGFR activation mediates inhibition of axon regeneration by myelin and chondroitin sulfate proteoglycans. Science 310, 106–110 (2005).

    Article  CAS  PubMed  Google Scholar 

  67. Carter, L. M. et al. The yellow fluorescent protein (YFP-H) mouse reveals neuroprotection as a novel mechanism underlying chondroitinase ABC-mediated repair after spinal cord injury. J. Neurosci. 28, 14107–14120 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Morishita, H. & Hensch, T. K. Critical period revisited: impact on vision. Curr. Opin. Neurobiol. 18, 101–107 (2008).

    Article  CAS  PubMed  Google Scholar 

  69. Harauzov, A. et al. Reducing intracortical inhibition in the adult visual cortex promotes ocular dominance plasticity. J. Neurosci. 30, 361–371 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Gogolla, N., Caroni, P., Luthi, A. & Herry, C. Perineuronal nets protect fear memories from erasure. Science 325, 1258–1261 (2009). Using ChABC injections in the amygdala, the authors revealed the role of the chondroitin sulphate-rich ECM in the formation of erasure-resistant emotional memories.

    Article  CAS  PubMed  Google Scholar 

  71. 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 

  72. 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 

  73. 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 

  74. Sternlicht, M. D. & Werb, Z. How matrix metalloproteinases regulate cell behavior. Annu. Rev. Cell Dev. Biol. 17, 463–516 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Streuli, C. Extracellular matrix remodelling and cellular differentiation. Curr. Opin. Cell Biol. 11, 634–640 (1999).

    Article  CAS  PubMed  Google Scholar 

  76. Ethell, I. M. & Ethell, D. W. Matrix metalloproteinases in brain development and remodeling: synaptic functions and targets. J. Neurosci. Res. 85, 2813–2823 (2007).

    Article  CAS  PubMed  Google Scholar 

  77. Szklarczyk, A., Lapinska, J., Rylski, M., McKay, R. D. & Kaczmarek, L. Matrix metalloproteinase-9 undergoes expression and activation during dendritic remodeling in adult hippocampus. J. Neurosci. 22, 920–930 (2002). This study reports on changes in the expression and the activity of MMP9 that are induced by activation of glutamate receptors with kainic acid.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Meighan, S. E. et al. Effects of extracellular matrix-degrading proteases matrix metalloproteinases 3 and 9 on spatial learning and synaptic plasticity. J. Neurochem. 96, 1227–1241 (2006). This article characterizes MMP9 as an essential player in hippocampal learning-related behaviour.

    Article  CAS  PubMed  Google Scholar 

  79. Nagy, V. et al. Matrix metalloproteinase-9 is required for hippocampal late-phase long-term potentiation and memory. J. Neurosci. 26, 1923–1934 (2006). One of the early reports in a series of articles demonstrating a role of MMP9 in hippocampal LTP.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Nagy, V., Bozdagi, O. & Huntley, G. W. The extracellular protease matrix metalloproteinase-9 is activated by inhibitory avoidance learning and required for long-term memory. Learn. Mem. 14, 655–664 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Bozdagi, O., Nagy, V., Kwei, K. T. & Huntley, G. W. In vivo roles for matrix metalloproteinase-9 in mature hippocampal synaptic physiology and plasticity. J. Neurophysiol. 98, 334–344 (2007).

    Article  CAS  PubMed  Google Scholar 

  82. Wang, X. B. et al. Extracellular proteolysis by matrix metalloproteinase-9 drives dendritic spine enlargement and long-term potentiation coordinately. Proc. Natl Acad. Sci. USA 105, 19520–19525 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Michaluk, P. et al. Matrix metalloproteinase-9 controls NMDA receptor surface diffusion through integrin β1 signaling. J. Neurosci. 29, 6007–6012 (2009). Using single quantum dot tracking, the authors demonstrate that MMP9 enzymatic activity increases surface trafficking of NMDA receptors.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Kramar, E. A., Bernard, J. A., Gall, C. M. & Lynch, G. Integrins modulate fast excitatory transmission at hippocampal synapses. J. Biol. Chem. 278, 10722–10730 (2003).

    Article  CAS  PubMed  Google Scholar 

  85. Tian, L. et al. Activation of NMDA receptors promotes dendritic spine development through MMP-mediated ICAM-5 cleavage. J. Cell Biol. 178, 687–700 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Gschwend, T. P., Krueger, S. R., Kozlov, S. V., Wolfer, D. P. & Sonderegger, P. Neurotrypsin, a novel multidomain serine protease expressed in the nervous system. Mol. Cell. Neurosci. 9, 207–219 (1997).

    Article  CAS  PubMed  Google Scholar 

  87. Proba, K., Gschwend, T. P. & Sonderegger, P. Cloning and sequencing of the cDNA encoding human neurotrypsin. Biochim. Biophys. Acta 1396, 143–147 (1998).

    Article  CAS  PubMed  Google Scholar 

  88. Molinari, F. et al. Truncating neurotrypsin mutation in autosomal recessive nonsyndromic mental retardation. Science 298, 1779–1781 (2002).

    Article  CAS  PubMed  Google Scholar 

  89. Bezakova, G. & Ruegg, M. A. New insights into the roles of agrin. Nature Rev. Mol. Cell Biol. 4, 295–308 (2003).

    Article  CAS  Google Scholar 

  90. Sanes, J. R. & Lichtman, J. W. Induction, assembly, maturation and maintenance of a postsynaptic apparatus. Nature Rev. Neurosci. 2, 791–805 (2001).

    Article  CAS  Google Scholar 

  91. Kummer, T. T., Misgeld, T. & Sanes, J. R. Assembly of the postsynaptic membrane at the neuromuscular junction: paradigm lost. Curr. Opin. Neurobiol. 16, 74–82 (2006).

    Article  CAS  PubMed  Google Scholar 

  92. Glass, D. J. et al. Agrin acts via a MuSK receptor complex. Cell 85, 513–523 (1996).

    Article  CAS  PubMed  Google Scholar 

  93. Kim, N. et al. Lrp4 is a receptor for Agrin and forms a complex with MuSK. Cell 135, 334–342 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Zhang, B. et al. LRP4 serves as a coreceptor of agrin. Neuron 60, 285–297 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Hilgenberg, L. G., Su, H., Gu, H., O'Dowd, D. K. & Smith, M. A. α3Na+/K+-ATPase is a neuronal receptor for agrin. Cell 125, 359–69 (2006).

    Article  CAS  PubMed  Google Scholar 

  96. Annies, M. et al. Clustering transmembrane-agrin induces filopodia-like processes on axons and dendrites. Mol. Cell. Neurosci. 31, 515–524 (2006).

    Article  CAS  PubMed  Google Scholar 

  97. Ksiazek, I. et al. Synapse loss in cortex of agrin-deficient mice after genetic rescue of perinatal death. J. Neurosci. 27, 7183–7195 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Reif, R. et al. Specific cleavage of agrin by neurotrypsin, a synaptic protease linked to mental retardation. FASEB J. 21, 3468–3478 (2007). This article characterizes the ECM proteoglycan agrin as a proteolytic target of the synaptic serine protease neurotrypsin.

    Article  CAS  PubMed  Google Scholar 

  99. Reif, R. et al. Purification and enzymological characterization of murine neurotrypsin. Protein Expr. Purif. 61, 13–21 (2008).

    Article  CAS  PubMed  Google Scholar 

  100. Stephan, A. et al. Neurotrypsin cleaves agrin locally at the synapse. FASEB J. 22, 1861–1873 (2008).

    Article  CAS  PubMed  Google Scholar 

  101. Frischknecht, R., Fejtova, A., Viesti, M., Stephan, A. & Sonderegger, P. Activity-induced synaptic capture and exocytosis of the neuronal serine protease neurotrypsin. J. Neurosci. 28, 1568–1579 (2008). This article demonstrates the activity-dependent recruitment of neurotrypsin to and exocytosis from presynaptic nerve endings, using neurotrypsin tagged with pHluorin, a pH-dependent variant of GFP, and live microscopy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Matsumoto-Miyai, K. et al. Coincident pre- and postsynaptic activation induces dendritic filopodia via neurotrypsin-dependent agrin cleavage. Cell 136, 1161–1171 (2009). This article describes the NMDA receptor-dependent activation of neurotrypsin that is released from presynaptic nerve endings in an inactive form and the importance of this enzyme and agrin 22 for LTP-dependent promotion of filopodia.

    Article  CAS  PubMed  Google Scholar 

  103. Holtmaat, A. & Svoboda, K. Experience-dependent structural synaptic plasticity in the mammalian brain. Nature Rev. Neurosci. 10, 647–658 (2009).

    Article  CAS  Google Scholar 

  104. Dityatev, A. & Fellin, T. Extracellular matrix in plasticity and epileptogenesis. Neuron Glia Biol. 4, 235–247 (2008).

    Article  PubMed  Google Scholar 

  105. Bonneh-Barkay, D. & Wiley, C. A. Brain extracellular matrix in neurodegeneration. Brain Pathol. 19, 573–585 (2009).

    Article  CAS  PubMed  Google Scholar 

  106. Pantazopoulos, H., Woo, T. U., Lim, M. P., Lange, N. & Berretta, S. Extracellular matrix-glial abnormalities in the amygdala and entorhinal cortex of subjects diagnosed with schizophrenia. Arch. Gen. Psychiatry 67, 155–166 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Triller, A. & Choquet, D. New concepts in synaptic biology derived from single-molecule imaging. Neuron 59, 359–374 (2008).

    Article  CAS  PubMed  Google Scholar 

  108. Gorkiewicz, T. et al. Matrix metalloproteinase-9 reversibly affects the time course of NMDA-induced currents in cultured rat hippocampal neurons. Hippocampus 30 Dec 2009 (doi:10.1002/hipo.2 0736).

  109. Miesenbock, G., De Angelis, D. A. & Rothman, J. E. Visualizing secretion and synaptic transmission with pH-sensitive green fluorescent proteins. Nature 394, 192–195 (1998).

    Article  CAS  PubMed  Google Scholar 

  110. Sankaranarayanan, S., De Angelis, D., Rothman, J. E. & Ryan, T. A. The use of pHluorins for optical measurements of presynaptic activity. Biophys. J. 79, 2199–2208 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Feng, G. et al. Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP. Neuron 28, 41–51 (2000).

    Article  CAS  PubMed  Google Scholar 

  112. De Paola, V., Arber, S. & Caroni, P. AMPA receptors regulate dynamic equilibrium of presynaptic terminals in mature hippocampal networks. Nature Neurosci. 6, 491–500 (2003).

    Article  CAS  PubMed  Google Scholar 

  113. Grutzendler, J., Kasthuri, N. & Gan, W. B. Long-term dendritic spine stability in the adult cortex. Nature 420, 812–816 (2002).

    Article  CAS  PubMed  Google Scholar 

  114. Frederiks, W. M. & Mook, O. R. Metabolic mapping of proteinase activity with emphasis on in situ zymography of gelatinases: review and protocols. J. Histochem. Cytochem. 52, 711–722 (2004).

    Article  CAS  PubMed  Google Scholar 

  115. Gawlak, M. et al. High resolution in situ zymography reveals matrix metalloproteinase activity at glutamatergic synapses. Neuroscience 158, 167–176 (2009).

    Article  CAS  PubMed  Google Scholar 

  116. Seong, J. et al. Visualization of Src activity at different compartments of the plasma membrane by FRET imaging. Chem. Biol. 16, 48–57 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Nakamura, T., Kurokawa, K., Kiyokawa, E. & Matsuda, M. Analysis of the spatiotemporal activation of rho GTPases using Raichu probes. Meth. Enzymol. 406, 315–332 (2006).

    Article  CAS  Google Scholar 

  118. Jones, F. S. & Jones, P. L. The tenascin family of ECM glycoproteins: structure, function, and regulation during embryonic development and tissue remodeling. Dev. Dyn. 218, 235–259 (2000).

    Article  CAS  PubMed  Google Scholar 

  119. Lau, C. G. & Zukin, R. S. NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders. Nature Rev. Neurosci. 8, 413–426 (2007).

    Article  CAS  Google Scholar 

  120. Groc, L., Bard, L. & Choquet, D. Surface trafficking of N-methyl-D-aspartate receptors: physiological and pathological perspectives. Neuroscience 158, 4–18 (2009).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank C. Sonderegger and L. Wanner for help with artwork. We gratefully acknowledge support by the Italian Institute of Technology (A.D.), the Deutsche Forschungsgemeinschaft (A.D. and M.S.), the New Jersey Commission for Spinal Cord Research and Stem Cell Research (M.S.), the Bundesministerium für Bildung und Forschung (M.S.) and the Swiss National Science Foundation (P.S.).

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Glossary

NPxY motif

A peptide motif with the amino acid sequence Asn–Pro–any amino acid–Tyr, which is important for protein–protein interactions.

Sensorimotor gating of the startle reflex

Inhibition of the startle reflex by a weak 'prepulse' stimulus that occurs 30–500 ms before the startling stimulus.

Reversal learning

The form of learning in which an organism shifts its response from a stimulus that is no longer rewarded to a previously unrewarded one.

Dendritic spine

A small protrusion of the dendritic membrane that represents the postsynaptic component of the majority of the excitatory synapses in the CNS.

RGD peptide

A peptide containing a motif with the amino acid sequence Arg–Gly–Asp. Such motifs in extracellular matrix proteins are important activators of integrin signalling.

Perineuronal nets

Aggregates of extracellular matrix molecules that embed cell bodies, axon initial segments and proximal dendrites of a subset of neurons in a mesh-like structure.

Focal adhesion

A large, dynamic protein complex through which the actin cytoskeleton of a cell connects to the extracellular matrix through integrins, providing a cell anchor and a sensor of extracellular signals.

Membrane ruffles

Processes that are formed by the movement of lamellipodia in the dynamic process of folding back onto the cell body from which they have extended.

Theta burst stimulation

Several bursts of high-frequency (for example, 100Hz) stimulation, which are delivered at 5 Hz to mimic the hippocampal theta rhythm that is thought to be important for learning and memory.

Granule cell

A tiny neuron found in specific brain areas, including the dentate gyrus, where it is the principle excitatory neuron.

Extinction memory

The memory that is formed when an animal learns that a conditioned stimulus no longer predicts a harmful stimulus.

Memory reconsolidation

The process in which previously consolidated memories are recalled and then actively consolidated, leading to their preservation.

Early and late LTP

Long-term potentiation (LTP) may be subdivided into an early phase, which lasts up to 3 hours, and a later phase, which follows the early one and may last days to months. The extension of early into late LTP requires gene transcription and protein synthesis.

Dendritic filopodium

A thin and 'headless' membrane protrusion that is not strictly part of a synapse but serves as a precursor of new dendritic spines during activity-dependent synaptogenesis.

Hebbian learning

The strengthening of synaptic connections when the presynaptic and the postsynaptic neuron are active simultaneously, which is often summarized as 'cells that fire together, wire together'.

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Dityatev, A., Schachner, M. & Sonderegger, P. The dual role of the extracellular matrix in synaptic plasticity and homeostasis. Nat Rev Neurosci 11, 735–746 (2010). https://doi.org/10.1038/nrn2898

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