Perisynaptic Chondroitin Sulfate Proteoglycans Restrict Structural Plasticity in an Integrin-Dependent Manner
Open accessAbstract
During early postnatal development of the CNS, neuronal networks are configured through the formation, elimination, and remodeling of dendritic spines, the sites of most excitatory synaptic connections. The closure of this critical period for plasticity correlates with the maturation of the extracellular matrix (ECM) and results in reduced dendritic spine dynamics. Chondroitin sulfate proteoglycans (CSPGs) are thought to be the active components of the mature ECM that inhibit functional plasticity in the adult CNS. These molecules are diffusely expressed in the extracellular space or aggregated as perineuronal nets around specific classes of neurons. We used organotypic hippocampal slices prepared from 6-d-old Thy1-YFP mice and maintained in culture for 4 weeks to allow ECM maturation. We performed live imaging of CA1 pyramidal cells to assess the effect of chondroitinase ABC (ChABC)-mediated digestion of CSPGs on dendritic spine dynamics. We found that CSPG digestion enhanced the motility of dendritic spines and induced the appearance of spine head protrusions in a glutamate receptor-independent manner. These changes were paralleled by the activation of β1-integrins and phosphorylation of focal adhesion kinase at synaptic sites, and were prevented by preincubation with a β1-integrin blocking antibody. Interestingly, microinjection of ChABC close to dendritic segments was sufficient to induce spine remodeling, demonstrating that CSPGs located around dendritic spines modulate their dynamics independently of perineuronal nets. This restrictive action of perisynaptic CSPGs in mature neural tissue may account for the therapeutic effects of ChABC in promoting functional recovery in impaired neural circuits.
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ChABC enhances dendritic spine number and motility at postsynaptic sites, while presynaptic terminals tend to show enhanced sprouting and synapse numbers.
“At postsynaptic sites, ChABC enhances dendritic spine number and motility, while presynaptic terminals tend to show enhanced sprouting and synapse numbers [40–42].”
From The extracellular matrix and perineuronal nets in memory (2022) · cites this paper as [40]
The Results section on spine dynamics reports that ChABC increased spine motility, but mean spine density was unchanged—not increased. The supplied passages do not establish the claimed presynaptic sprouting or increase in synapse numbers. Page numbers are not provided in our copy's excerpts. (LLM, conf=0.90)
Experimental — accuracy not yet measuredRemoving PNNs in the hippocampus with ChABC changes spine dynamics by restricting β1-integrin activation and signaling at synapses.
“a series of elegant experiments by Orlando and colleagues recently found that removal of PNNs in the hippocampus using ChABC resulted in altered spine dynamics via a restriction of β1-integrin activation and signaling at synaptic sites (Orlando et al., 2012).”
From Perineuronal nets and schizophrenia: The importance of neuronal coatings (2014) · cites this paper as Orlando et al., 2012
CSPG digestion in organotypic hippocampal slices enhances motility of dendritic spines of CA1 pyramidal cells and induces spine head protrusions, in parallel with activation of β1-integrins and phosphorylation of focal adhesion kinase at synaptic sites.
“CSPG digestion in organotypic hippocampal slices enhances the motility of dendritic spines of CA1 pyramidal cells and induces the appearance of spine head protrusions, in parallel with the activation of β1-integrins and phosphorylation of focal adhesion kinase at synaptic sites (Orlando et al., 2012).”
From The hyaluronan and proteoglycan link proteins: Organizers of the brain extracellular matrix and key molecules for neuronal function and plasticity (2015) · cites this paper as Orlando et al., 2012
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References 47 · Cited by 153
Research works printed but not linked: 25
- Bradbury EJ, Moon LD, Popat RJ, King VR, Bennett GS, Patel PN, Fawcett JW, McMahon SB (2002) Chondroitinase ABC promotes functional re- covery after spinal cord injury. Nature 416:636 -640. CrossRef Medline · DOI · Paper page
- Brakebusch C, Seidenbecher CI, Asztely F, Rauch U, Matthies H, Meyer H, Krug M, Bo ¨ckers TM, Zhou X, Kreutz MR, Montag D, Gundelfinger ED, Fa ¨ssler R (2002) Brevican-deficient mice display impaired hippocampal CA1 long-term potentiation but show no obvious deficits in learning and memory. Mol Cell Biol 22:7417-7427. CrossRef Medline · DOI · Paper page
- Bru ¨ckner G, Grosche J, Hartlage-Ru ¨bsamen M, Schmidt S, Schachner M (2003) Region and lamina-specific distribution of extracellular matrix proteoglycans, hyaluronan and tenascin-R in the mouse hippocampal formation. J Chem Neuroanat 26:37-50. CrossRef Medline · DOI
- Carulli D, Pizzorusso T, Kwok JC, Putignano E, Poli A, Forostyak S, Andrews MR, Deepa SS, Glant TT, Fawcett JW (2010) Animals lacking link pro- tein have attenuated perineuronal nets and persistent plasticity. Brain 133:2331-2347. CrossRef Medline · DOI · Paper page
- Cho S, Wood A, Bowlby MR (2007) Brain slices as models for neurodegen- erative disease and screening platforms to identify novel therapeutics. Curr Neuropharmacol 5:19 -33. CrossRef Medline · DOI
- De Simoni A, Griesinger CB, Edwards FA (2003) Development of rat CA1 neurones in acute versus organotypic slices: role of experience in synaptic morphology and activity. J Physiol 550:135-147. CrossRef Medline · DOI
- Frischknecht R, Gundelfinger ED (2012) The brain's extracellular matrix and its role in synaptic plasticity. Adv Exp Med Biol 970:153-171. CrossRef Medline · DOI · Paper page
- Ga ¨hwiler BH, Capogna M, Debanne D, McKinney RA, Thompson SM (1997) Organotypic slice cultures: a technique has come of age. Trends Neurosci 20:471-477. CrossRef Medline · DOI
- Galtrey CM, Fawcett JW (2007) The role of chondroitin sulfate proteogly- cans in regeneration and plasticity in the central nervous system. Brain Res Rev 54:1-18. CrossRef Medline · DOI · Paper page
- García-Alías G, Fawcett JW (2012) Training and anti-CSPG combination therapy for spinal cord injury. Exp Neurol 235:26 -32. CrossRef Medline · DOI
- Ha ¨rtig W, Derouiche A, Welt K, Brauer K, Grosche J, Ma ¨der M, Reichenbach A, Bru ¨ckner G (1999) Cortical neurons immunoreactive for the potas- sium channel Kv3.1b subunit are predominantly surrounded by perineuro- nal nets presumed as a buffering system for cations. Brain Res 842:15-29. CrossRef Medline · DOI · Paper page
- Hensch TK (2005) Critical period plasticity in local cortical circuits. Nat Rev Neurosci 6:877-888. CrossRef Medline · DOI · Paper page
- Hu F, Strittmatter SM (2008) The N-terminal domain of Nogo-A inhibits cell adhesion and axonal outgrowth by an integrin-specific mechanism. J Neurosci 28:1262-1269. CrossRef Medline · DOI
- Huang Z, Shimazu K, Woo NH, Zang K, Mu ¨ller U, Lu B, Reichardt LF (2006) Distinct roles of the 1-class integrins at the developing and the mature hippocampal excitatory synapse. J Neurosci 26:11208 -11219. CrossRef Medline · DOI
- Krama ´r 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 103:5579 -5584. CrossRef Medline · DOI · Paper page
- Kwok JC, Dick G, Wang D, Fawcett JW (2011) Extracellular matrix and perineuronal nets in CNS repair. Dev Neurobiol 71:1073-1089. CrossRef Medline · DOI · Paper page
- Lee H, Raiker SJ, Venkatesh K, Geary R, Robak LA, Zhang Y, Yeh HH, Shrager P, Giger RJ (2008) Synaptic function for the Nogo-66 receptor NgR1: regulation of dendritic spine morphology and activity-dependent synap- tic strength. J Neurosci 28:2753-2765. CrossRef Medline · DOI
- Mitra SK, Hanson DA, Schlaepfer DD (2005) Focal adhesion kinase: in command and control of cell motility. Nat Rev Mol Cell Biol 6:56 -68. CrossRef Medline · DOI
- Moon LD, Asher RA, Rhodes KE, Fawcett JW (2001) Regeneration of CNS axons back to their target following treatment of adult rat brain with chondroitinase ABC. Nat Neurosci 4:465-466. CrossRef Medline · DOI
- 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 520:2041-2052. CrossRef Medline · DOI
- Pradhan AD, Case AM, Farrer RG, Tsai SY, Cheatwood JL, Martin JL, Kartje GL (2010) Dendritic spine alterations in neocortical pyramidal neurons following postnatal neuronal Nogo-A knockdown. Dev Neurosci 32:313- 320. CrossRef Medline · DOI
- Richards DA, Mateos JM, Hugel S, de Paola V, Caroni P, Ga ¨hwiler BH, McKinney RA (2005) Glutamate induces the rapid formation of spine head protrusions in hippocampal slice cultures. Proc Natl Acad Sci U S A 102:6166 -6171. CrossRef Medline · DOI · Paper page
- Sale A, Maya Vetencourt JF, Medini P, Cenni MC, Baroncelli L, De Pasquale R, Maffei L (2007) Environmental enrichment in adulthood promotes amblyopia recovery through a reduction of intracortical inhibition. Nat Neurosci 10:679 -681. CrossRef Medline · DOI · Paper page
- Warren MS, Bradley WD, Gourley SL, Lin YC, Simpson MA, Reichardt LF, Greer CA, Taylor JR, Koleske AJ (2012) Integrin beta1 signals through Arg to regulate postnatal dendritic arborization, synapse density, and behavior. J Neurosci 32:2824 -2834. CrossRef Medline · DOI
- Wu Y, Chen L, Zheng PS, Yang BB (2002) 1-Integrin-mediated glioma cell adhesion and free radical-induced apoptosis are regulated by binding to a C-terminal domain of PG-M/versican. J Biol Chem 277:12294 -12301. CrossRef Medline · DOI
- Authors
- Orlando, C., Ster, J., Gerber, U., Fawcett, J. W., & Raineteau, O.
- Affiliations
- University of Zurich (CH)
- University of Cambridge (GB)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-12-12
- Volume
- 32
- Issue
- 50
- Pages
- 18009-18017
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6621736
- OpenAlex
- W2007162991
- Cited by
- 153
- References
- 47
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 10 · 2023: 16 · 2022: 16 · 2021: 10 · 2020: 14 · 2019: 5 · 2018: 14 · 2017: 11 · 2016: 4 · 2015: 13 · 2014: 19 · 2013: 9
- FWCI
- 6.21
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Repository for Publications and Research Data (ETH Zurich) (submittedVersion, cc-by-nc-sa)
- ETH Zürich Research Collection
- Funders
- Christopher and Dana Reeve Foundation
- University of Cambridge
- Isaac Newton Trust
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- chondroitin sulfate proteoglycans, dendritic spine dynamics, synaptic plasticity, chondroitinase ABC, beta1 integrin, focal adhesion kinase, extracellular matrix maturation, perineuronal nets, CA1 pyramidal neurons, hippocampus, postnatal brain development
- MeSH terms
- Animals, Extracellular Matrix, Fluorescent Antibody Technique, Neuronal Plasticity, Organ Culture Techniques, Chondroitin Sulfate Proteoglycans, Blotting, Western, Pyramidal Cells, Patch-Clamp Techniques, Microscopy, Confocal, Integrin beta1, Chondroitin ABC Lyase, Dendritic Spines, Mice, Focal Adhesion Protein-Tyrosine Kinases, CA1 Region, Hippocampal
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