Abstract
Neurons and glial cells secrete numerous molecules that accumulate in the extracellular space and form the neural extracellular matrix (ECM). There are diverse forms of the ECM. The most conspicuous aggregates of ECM molecules, containing chondroitin sulfate proteoglycans, hyaluronic acid, link proteins, and tenascin-R, are found around perisomatic GABAergic synapses on fast-spiking interneurons. However, also the perisynaptic extracellular space of glutamatergic synapses is enriched in ECM molecules such as hyaluronic acid and brevican. These ECM molecules and their receptors, the most studied of which are integrins, regulate the induction and maintenance of synaptic modifications. Recent data highlight the importance of synaptically secreted extracellular matrix molecule LGI1 in organization of synaptic machinery. Accumulated functional data point to the view that a synapse is a tetrapartite system including the pre- and postsynapse, associated astroglial terminals, and the ECM, in which there is an exchange of signals between all four components. This review is to give a short introduction to neural ECM; to summarize available electron microscopy data on expression of perisynaptic and synaptic ECM molecules and their receptors, as a reference for other super-resolution methods; and to present a protocol for STORM imaging of (peri)synaptic ECM using a commercially available super-resolution microscope (Nikon N-STORM).
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References
Faissner A, Pyka M, Geissler M, Sobik T, Frischknecht R, Gundelfinger ED, Seidenbecher C (2010) Contributions of astrocytes to synapse formation and maturation – potential functions of the perisynaptic extracellular matrix. Brain Res Rev 63:26–38. doi:S0165-0173(10)00002-0 [pii] 10.1016/j.brainresrev.2010.01.001
Dityatev A, Schachner M (2003) Extracellular matrix molecules and synaptic plasticity. Nat Rev Neurosci 4(6):456–468. doi:10.1038/nrn1115 nrn1115 [pii]
Dityatev A, Frischknecht R, Seidenbecher CI (2006) Extracellular matrix and synaptic functions. Results Probl Cell Differ 43:69–97
Yamaguchi Y (2000) Lecticans: organizers of the brain extracellular matrix. Cell Mol Life Sci 57(2):276–289
Galtrey CM, Fawcett JW (2007) The role of chondroitin sulfate proteoglycans in regeneration and plasticity in the central nervous system. Brain Res Rev 54(1):1–18. doi:S0165-0173(06)00109-3 [pii] 10.1016/j.brainresrev.2006.09.006
Bruckner G, Szeoke S, Pavlica S, Grosche J, Kacza J (2006) Axon initial segment ensheathed by extracellular matrix in perineuronal nets. Neuroscience 138(2):365–375. doi:S0306-4522(05)01346-1 [pii] 10.1016/j.neuroscience.2005.11.068
Lundell A, Olin AI, Morgelin M, al-Karadaghi S, Aspberg A, Logan DT (2004) Structural basis for interactions between tenascins and lectican C-type lectin domains: evidence for a crosslinking role for tenascins. Structure 12(8):1495–1506
Bornstein P, Sage EH (2002) Matricellular proteins: extracellular modulators of cell function. Curr Opin Cell Biol 14(5):608–616. doi:S0955067402003617 [pii]
Murakami T, Ohtsuka A (2003) Perisynaptic barrier of proteoglycans in the mature brain and spinal cord. Arch Histol Cytol 66(3):195–207
Brakebusch C, Seidenbecher CI, Asztely F, Rauch U, Matthies H, Meyer H, Krug M, Bockers TM, Zhou X, Kreutz MR, Montag D, Gundelfinger ED, Fassler R (2002) Brevican-deficient mice display impaired hippocampal CA1 long-term potentiation but show no obvious deficits in learning and memory. Mol Cell Biol 22(21):7417–7427
Hagihara K, Miura R, Kosaki R, Berglund E, Ranscht B, Yamaguchi Y (1999) Immunohistochemical evidence for the brevican-tenascin-R interaction: colocalization in perineuronal nets suggests a physiological role for the interaction in the adult rat brain. J Comp Neurol 410(2):256–264
Morita S, Oohira A, Miyata S (2010) Activity-dependent remodeling of chondroitin sulfate proteoglycans extracellular matrix in the hypothalamo-neurohypophysial system. Neuroscience 166(4):1068–1082. doi:10.1016/j.neuroscience.2010.01.041
Matsui F, Nishizuka M, Yasuda Y, Aono S, Watanabe E, Oohira A (1998) Occurrence of a N-terminal proteolytic fragment of neurocan, not a C-terminal half, in a perineuronal net in the adult rat cerebrum. Brain Res 790(1–2):45–51
Atoji Y, Yamamoto Y, Suzuki Y, Matsui F, Oohira A (1997) Immunohistochemical localization of neurocan in the lower auditory nuclei of the dog. Hear Res 110(1–2):200–208
Schuster T, Krug M, Stalder M, Hackel N, Gerardy-Schahn R, Schachner M (2001) Immunoelectron microscopic localization of the neural recognition molecules L1, NCAM, and its isoform NCAM180, the NCAM-associated polysialic acid, beta1 integrin and the extracellular matrix molecule tenascin-R in synapses of the adult rat hippocampus. J Neurobiol 49(2):142–158
Lively S, Ringuette MJ, Brown IR (2007) Localization of the extracellular matrix protein SC1 to synapses in the adult rat brain. Neurochem Res 32(1):65–71. doi: 10.1007/s11064-006-9226-4
Lively S, Brown IR (2010) The extracellular matrix protein SC1/Hevin localizes to multivesicular bodies in Bergmann glial fibers in the adult rat cerebellum. Neurochem Res 35(2):315–322. doi:10.1007/s11064-009-0057-y
Xu D, Hopf C, Reddy R, Cho RW, Guo L, Lanahan A, Petralia RS, Wenthold RJ, O’Brien RJ, Worley P (2003) Narp and NP1 form heterocomplexes that function in developmental and activity-dependent synaptic plasticity. Neuron 39(3):513–528
O’Brien RJ, Xu D, Petralia RS, Steward O, Huganir RL, Worley P (1999) Synaptic clustering of AMPA receptors by the extracellular immediate-early gene product Narp. Neuron 23(2):309–323
Malatesta M, Furlan S, Mariotti R, Zancanaro C, Nobile C (2009) Distribution of the epilepsy-related Lgi1 protein in rat cortical neurons. Histochem Cell Biol 132(5):505–513. doi:10.1007/s00418-009-0637-6
Fukata Y, Lovero KL, Iwanaga T, Watanabe A, Yokoi N, Tabuchi K, Shigemoto R, Nicoll RA, Fukata M (2010) Disruption of LGI1-linked synaptic complex causes abnormal synaptic transmission and epilepsy. Proc Natl Acad Sci U S A 107(8):3799–3804. doi:10.1073/pnas.0914537107
Einheber S, Schnapp LM, Salzer JL, Cappiello ZB, Milner TA (1996) Regional and ultrastructural distribution of the alpha 8 integrin subunit in developing and adult rat brain suggests a role in synaptic function. J Comp Neurol 370(1):105–134. doi:10.1002/(SICI)1096-9861(19960617)370:1<105::AID-CNE10>3.0.CO;2-R
Einheber S, Pierce JP, Chow D, Znamensky V, Schnapp LM, Milner TA (2001) Dentate hilar mossy cells and somatostatin-containing neurons are immunoreactive for the alpha8 integrin subunit: characterization in normal and kainic acid-treated rats. Neuroscience 105(3):619–638
Hellwig S, Hack I, Kowalski J, Brunne B, Jarowyj J, Unger A, Bock HH, Junghans D, Frotscher M (2011) Role for Reelin in neurotransmitter release. J Neurosci 31(7):2352–2360. doi:10.1523/JNEUROSCI.3984-10.2011
Mortillo S, Elste A, Ge Y, Patil SB, Hsiao K, Huntley GW, Davis RL, Benson DL (2012) Compensatory redistribution of neuroligins and N-cadherin following deletion of synaptic beta1-integrin. J Comp Neurol 520(9):2041–2052. doi:10.1002/cne.23027
Nishimura SL, Boylen KP, Einheber S, Milner TA, Ramos DM, Pytela R (1998) Synaptic and glial localization of the integrin alphavbeta8 in mouse and rat brain. Brain Res 791(1–2):271–282
Schulte U, Thumfart JO, Klocker N, Sailer CA, Bildl W, Biniossek M, Dehn D, Deller T, Eble S, Abbass K, Wangler T, Knaus HG, Fakler B (2006) The epilepsy-linked Lgi1 protein assembles into presynaptic Kv1 channels and inhibits inactivation by Kvbeta1. Neuron 49(5):697–706. doi:S0896-6273(06)00090-0 [pii] 10.1016/j.neuron.2006.01.033
Sagane K, Hayakawa K, Kai J, Hirohashi T, Takahashi E, Miyamoto N, Ino M, Oki T, Yamazaki K, Nagasu T (2005) Ataxia and peripheral nerve hypomyelination in ADAM22-deficient mice. BMC Neurosci 6:33. doi:1471-2202-6-33 [pii] 10.1186/1471-2202-6-33
Owuor K, Harel NY, Englot DJ, Hisama F, Blumenfeld H, Strittmatter SM (2009) LGI1-associated epilepsy through altered ADAM23-dependent neuronal morphology. Mol Cell Neurosci 42(4):448–457. doi:S1044-7431(09)00213-9 [pii] 10.1016/j.mcn.2009.09.008
Dityatev A, Fellin T (2008) Extracellular matrix in plasticity and epileptogenesis. Neuron Glia Biol 4(3):235–247. doi:S1740925X09000118 [pii] 10.1017/S1740925X09000118
Fukata Y, Adesnik H, Iwanaga T, Bredt DS, Nicoll RA, Fukata M (2006) Epilepsy-related ligand/receptor complex LGI1 and ADAM22 regulate synaptic transmission. Science 313(5794):1792–1795. doi:313/5794/1792 [pii] 10.1126/science.1129947
Shi Y, Ethell IM (2006) Integrins control dendritic spine plasticity in hippocampal neurons through NMDA receptor and Ca2+/calmodulin-dependent protein kinase II-mediated actin reorganization. J Neurosci 26(6):1813–1822. doi:26/6/1813 [pii] 10.1523/JNEUROSCI.4091-05.2006
Kramar EA, Lin B, Rex CS, Gall CM, Lynch G (2006) Integrin-driven actin polymerization consolidates long-term potentiation. Proc Natl Acad Sci U S A 103(14):5579–5584. doi:0601354103 [pii] 10.1073/pnas.0601354103
Cingolani LA, Thalhammer A, Yu LM, Catalano M, Ramos T, Colicos MA, Goda Y (2008) Activity-dependent regulation of synaptic AMPA receptor composition and abundance by beta3 integrins. Neuron 58(5):749–762. doi:S0896-6273(08)00337-1 [pii] 10.1016/j.neuron.2008.04.011
Diaspro A, Athanassiou A (2010) Introduction to special issue on nanophysics. Microsc Res Tech 73(10):929–930. doi: 10.1002/jemt.20909
van Zanten TS, Cambi A, Koopman M, Joosten B, Figdor CG, Garcia-Parajo MF (2009) Hotspots of GPI-anchored proteins and integrin nanoclusters function as nucleation sites for cell adhesion. Proc Natl Acad Sci U S A 106(44):18557–18562. doi:10.1073/pnas.0905217106
Masi A, Cicchi R, Carloni A, Pavone FS, Arcangeli A (2010) Optical methods in the study of protein-protein interactions. Adv Exp Med Biol 674:33–42
Schroder J, Benink H, Dyba M, Los GV (2009) In vivo labeling method using a genetic construct for nanoscale resolution microscopy. Biophys J 96(1):L01–L03. doi:10.1016/j.bpj.2008.09.032
Bates M, Huang B, Dempsey GT, Zhuang X (2007) Multicolor super-resolution imaging with photo-switchable fluorescent probes. Science 317(5845):1749–1753. doi:10.1126/science.1146598
Huang B, Jones SA, Brandenburg B, Zhuang X (2008) Whole-cell 3D STORM reveals interactions between cellular structures with nanometer-scale resolution. Nat Methods 5(12):1047–1052. doi:10.1038/nmeth.1274
Cella Zanacchi F, Lavagnino Z, Perrone Donnorso M, Del Bue A, Furia L, Faretta M, Diaspro A (2011) Live-cell 3D super-resolution imaging in thick biological samples. Nat Methods 8(12):1047–1049. doi:10.1038/nmeth.1744
Betzig E, Patterson GH, Sougrat R, Lindwasser OW, Olenych S, Bonifacino JS, Davidson MW, Lippincott-Schwartz J, Hess HF (2006) Imaging intracellular fluorescent proteins at nanometer resolution. Science 313(5793):1642–1645. doi:10.1126/science.1127344
Rust MJ, Bates M, Zhuang X (2006) Sub-diffraction-limit imaging by stochastic optical reconstruction microscopy (STORM). Nat Methods 3(10):793–795. doi:10.1038/nmeth929
Hess ST, Girirajan TP, Mason MD (2006) Ultra-high resolution imaging by fluorescence photoactivation localization microscopy. Biophys J 91(11):4258–4272. doi:10.1529/biophysj.106.091116
Folling J, Bossi M, Bock H, Medda R, Wurm CA, Hein B, Jakobs S, Eggeling C, Hell SW (2008) Fluorescence nanoscopy by ground-state depletion and single-molecule return. Nat Methods 5(11):943–945. doi:10.1038/nmeth.1257
Zhu L, Zhang W, Elnatan D, Huang B (2012) Faster STORM using compressed sensing. Nat Methods 9(7):721–723
Baddeley D, Crossman D, Rossberger S, Cheyne JE, Montgomery JM, Jayasinghe ID, Cremer C, Cannell MB, Soeller C (2011) 4D super-resolution microscopy with conventional fluorophores and single wavelength excitation in optically thick cells and tissues. PLoS One 6(5):e20645
Nanguneri S, Flottmann B, Horstmann H, Heilemann M, Kuner T (2012) Three-dimensional, tomographic super-resolution fluorescence imaging of serially sectioned thick samples. PLoS One 7(5):e38098
Acknowledgments
This study was supported by the Russian Federation governmental grant No. 11.G34.31.0012 and by COST Action BM1001 “Brain Extracellular Matrix in Health and Disease.” We kindly acknowledge Nikon Instruments for N-STORM measurements performed within the activities of the Advanced Nikon Centre at IIT.
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Korotchenko, S., Zanacchi, F.C., Diaspro, A., Dityatev, A. (2014). Zooming in on the (Peri)synaptic Extracellular Matrix. In: Nägerl, U., Triller, A. (eds) Nanoscale Imaging of Synapses. Neuromethods, vol 84. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4614-9179-8_10
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DOI: https://doi.org/10.1007/978-1-4614-9179-8_10
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