Chondroitin sulphate proteoglycans: Key modulators of spinal cord and brain plasticity

Bartus, Katalin; James, Nicholas D.; Bosch, Karen; Bradbury, Elizabeth J.

doi:10.1016/j.expneurol.2011.08.008

Cited by 99 publications

(67 citation statements)

References 189 publications

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“…it is well-established that chondroitinase ABC (ChABC) significantly ameliorates the hostile-matrix microenvironment following SCI by enzymatically digesting the glycosaminoglycan side-chains of CSPGs and promotes functional recovery [4,111,112] . in accord with these findings, a recent study showed that the infusion of ChABC is also successful in restoring neuronal glycosylation to normal [113] .…”

Section: Pharmacological Strategiesmentioning

confidence: 99%

The glial scar in spinal cord injury and repair

2013

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Glial scarring following severe tissue damage and inflammation after spinal cord injury (SCi) is due to an extreme, uncontrolled form of reactive astrogliosis that typically occurs around the injury site. The scarring process includes the misalignment of activated astrocytes and the deposition of inhibitory chondroitin sulfate proteoglycans. Here, we first discuss recent developments in the molecular and cellular features of glial scar formation, with special focus on the potential cellular origin of scar-forming cells and the molecular mechanisms underlying glial scar formation after SCi. Second, we discuss the role of glial scar formation in the regulation of axonal regeneration and the cascades of neuro-inflammation. Last, we summarize the physical and pharmacological approaches targeting the modulation of glial scarring to better understand the role of glial scar formation in the repair of SCi.Keywords: glial scar; spinal cord injury; axonal regeneration; astrocyte activation; reactive astrogliosis; neuroinflammation IntroductionSpinal cord injury (SCi) is a common and devastating central nervous system (CNS) insult that results in disruption of cord microstructure and is followed by limited neuronal regeneration and insufficient functional recovery in adult mammals. After severe SCi, and in response to changes in the local microenvironment, astrocytes, the most abundant glial cells in the CNS, transform into reactive astrocytes and undergo dramatic morphological changes [1] as well as massive variations in gene expression [2] . Reactive astrocytes, the major component of glial scars, along with other cells in the spinal cord and blood-borne cells leaking from the damaged blood-spinal cord barrier, participate in the process of scar formation [3] .From the historical perspective, a glial scar is recognized as an impediment to the regeneration of axons in the cord because of the irregular rearrangement of hypertrophic astrocytic processes, as well as major components of the axonal inhibitory extracellular matrix (ECM), including chondroitin sulfate proteoglycans (CSPGs) that are secreted by the reactive astrocytes [4] . Currently, increasing evidence is advancing our knowledge of the mechanism of the formation of glial scars after a lesion and the roles of glial scars in the regulation of neuro-inflammation and repair processes [5,6] .This article reviews the following: (1) the molecular and cellular properties of glial scar formation following SCi;(2) the roles of glial scar formation in axonal regeneration and neuro-inflammation; and (3) the current status of scarmodulating therapeutic strategies for spinal cord repair after injury. Molecular and Cellular Properties of Glial Scars Characterization of Glial ScarsTraumatic damage of the spinal cord can result in seallike scar tissue in the lesion zone, which is filled with dense cellular components and a connective matrix. Generally, the scar tissue is classified into two parts, fibrotic and glial. 422The fibrotic scar, primarily composed of invading fibrobl...

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Section: Pharmacological Strategiesmentioning

confidence: 99%

The glial scar in spinal cord injury and repair

2013

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“…1 and 2), with synapses forming through gaps in the PNN (6)(7)(8)(9)(10)(11)(12). The PNN is initially laid down at the end of critical periods in wiring of sensory inputs and may have contributions from both neurons and glia (13).…”

mentioning

confidence: 99%

“…This statement from a chapter by Sejnowski (25) in a book entitled What We Believe but Cannot Prove was highly insightful but gave no mechanistic detail on how the ECM might store the information. The only experimental test proposed was that disruption of the ECM would interfere with memory, for which there is (and already was) much evidence (6,12,(14)(15)(16), but the evidence is not incisive enough to be convincing. Meanwhile, reviews on MMPs in synaptic plasticity and learning conclude that the key substrates and downstream mechanisms remain unclear (7,16,26).…”

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confidence: 99%

Very long-term memories may be stored in the pattern of holes in the perineuronal net

Tsien

2013

Proc. Natl. Acad. Sci. U.S.A.

210

189

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A hypothesis and the experiments to test it propose that very long-term memories, such as fear conditioning, are stored as the pattern of holes in the perineuronal net (PNN), a specialized ECM that envelops mature neurons and restricts synapse formation. The 3D intertwining of PNN and synapses would be imaged by serial-section EM. Lifetimes of PNN vs. intrasynaptic components would be compared with pulse-chase 15 N labeling in mice and 14 C content in human cadaver brains. Genetically encoded indicators and antineoepitope antibodies should improve spatial and temporal resolution of the in vivo activity of proteases that locally erode PNN. Further techniques suggested include genetic KOs, better pharmacological inhibitors, and a genetically encoded snapshot reporter, which will capture the pattern of activity throughout a large ensemble of neurons at a time precisely defined by the triggering illumination, drive expression of effector genes to mark those cells, and allow selective excitation, inhibition, or ablation to test their functional importance. The snapshot reporter should enable more precise inhibition or potentiation of PNN erosion to compare with behavioral consequences. Finally, biosynthesis of PNN components and proteases would be imaged.

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“…Beside mentioned, the upregulation of several proteins, including chondroitin sulfate proteoglycans (CSPG) is reported as well (5-7). In the adult brain, basic levels of CSPGs are necessary, since they maintain the structure of extracellular matrix (ECM), stabilize synapse and proper axonal sprouting, and therefore manage plasticity (8,9). It is believed that all of the major brain cell types contribute to the production of these normal levels of CSPG (9).…”

Section: Kratak Sadr`ajmentioning

confidence: 99%

Real-Time PCR and Immunocytochemical Study of Chondroitin Sulfate Proteoglycans after Scratch Wounding in Cultured Astrocytes / PCR I IMUNOCITOHEMIJSKA STUDIJA EKSPRESIJE HONDROITIN-SULFATNIH PROTEOGLIKANA NAKON POVREDE ASTROCITA U KULTURI

Parabucki¹,

Santrač²,

Savić³

et al. 2013

Journal of Medical Biochemistry

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SummaryBackground: Various in vivo and in vitro models have been described in order to elucidate the pathobiology underlying the traumatic brain injury (TBI) and test potentially suitable treatments. Since TBI is a complex disease, models differ in regard to the aspect of TBI that is being investigated. One of the used in vitro models is the scratch wound assay, first established as a reproducible, low-cost assay for the analysis of cell migration in vitro. The aim of the present study was to further investigate the relevancy of this model as a counterpart of in vivo TBI models. Methods: We have examined the astrocytic response to a mechanical injury in terms of expression of chondroitin sulfate proteoglycans (CSPGs) -phosphacan, neurocan and brevican, using real-time PCR and immunocytochemistry. Results: Our results indicate that in vitro scratch wounding alters the expression profile of examined CSPGs. Four hours after the scratch injury of the astrocytic monolayer, real-time PCR analysis revealed upregulation of mRNA levels for phosphacan (3-fold) and neurocan (2-fold), whereas brevican mRNA was downregulated (2-fold). Immunofluorescent signal for phosphacan and neurocan was more intense in astrocytes close to the injury site, while brevican was scarcely present in cultured astrocytes. Conclusions: Obtained results indicate that CSPGs are differentially expressed by astrocytes after scratch wounding,

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Chondroitin sulphate proteoglycans: Key modulators of spinal cord and brain plasticity

Cited by 99 publications

References 189 publications

The glial scar in spinal cord injury and repair

The glial scar in spinal cord injury and repair

Very long-term memories may be stored in the pattern of holes in the perineuronal net

Real-Time PCR and Immunocytochemical Study of Chondroitin Sulfate Proteoglycans after Scratch Wounding in Cultured Astrocytes / PCR I IMUNOCITOHEMIJSKA STUDIJA EKSPRESIJE HONDROITIN-SULFATNIH PROTEOGLIKANA NAKON POVREDE ASTROCITA U KULTURI

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