Chondroitinase ABC Digestion of the Perineuronal Net Promotes Functional Collateral Sprouting in the Cuneate Nucleus after Cervical Spinal Cord Injury

Massey, James M.; Hubscher, Charles H.; Wagoner, Michelle R.; Decker, Julie A.; Amps, Jeremy; Silver, Jerry; Onifer, Stephen M.

doi:10.1523/jneurosci.5467-05.2006

Cited by 286 publications

(257 citation statements)

References 55 publications

(84 reference statements)

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“…Additionally, collateral sprouting of intact axons has been observed. We found that chABC injections at the brainstem after cervical spinal cord dorsal quadrant lesions promoted collateral sprouting of forepaw primary afferents remaining in the target cuneate nuclei [77]. Moreover, receptive field mapping showed that this sprouting led to more cuneate nuclei neurons responding physiologically to forepaw digits tactile stimulation.…”

Section: Pharmacological and Gene-delivery Approachesmentioning

confidence: 77%

Plasticity After Spinal Cord Injury: Relevance to Recovery and Approaches to Facilitate It

2011

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Summary: Motor, sensory, and autonomic functions can spontaneously return or recover to varying extents in both humans and animals, regardless of the traumatic spinal cord injury (SCI) level and whether it was complete or incomplete. In parallel, adverse and painful functions can appear. The underlying mechanisms for all of these diverse functional changes are summarized under the term plasticity. Our review will describe what is known regarding this phenomenon after traumatic SCI and focus on its relevance to motor and sensory recovery. Although it is still somewhat speculative, plasticity can be found throughout the neuraxis and includes various changes ranging from alterations in the properties of spared neuronal circuitries, intact or lesioned axon collateral sprouting, and synaptic rearrangements. Furthermore, we will discuss a selection of potential approaches for facilitating plasticity as possible SCI treatments. Because a mechanism underlying spontaneous plasticity and recovery might be motor activity and the related neuronal activity, activity-based therapies are being used and investigated both clinically and experimentally. Additional pharmacological and gene-delivery approaches, based on plasticity being dependent on the delicate balance between growth inhibition and promotion as well as the basic intrinsic growth ability of the neurons themselves, have been found to be effective alone and in combination with activitybased therapies. The positive results have to be tempered with the reality that not all plasticity is beneficial. Therefore, a tremendous number of questions still need to be addressed. Ultimately, answers to these questions will enhance plasticity's potential for improving the quality of life for persons with SCI.

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Section: Pharmacological and Gene-delivery Approachesmentioning

confidence: 77%

Plasticity After Spinal Cord Injury: Relevance to Recovery and Approaches to Facilitate It

2011

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“…Evidence suggests that CSPGs are up-regulated within PNNs both near and far from a CNS lesion (Massey et al, 2006). Enzymatic digestion of PNNs by chondroitinase ABC leads to reactivation of plasticity in adult animals (Corvetti and Rossi, 2005;Pizzorusso et al, 2002), and enhances spared fiber collateral sprouting and synapse formation in injured animals (Tropea et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Conditional Sox9 ablation reduces chondroitin sulfate proteoglycan levels and improves motor function following spinal cord injury

McKillop

Dragan

Schedl

et al. 2012

Glia

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Chondroitin sulfate proteoglycans (CSPGs) found in perineuronal nets and in the glial scar after spinal cord injury have been shown to inhibit axonal growth and plasticity. Since we have previously identified SOX9 as a transcription factor that upregulates the expression of a battery of genes associated with glial scar formation in primary astrocyte cultures, we predicted that conditional Sox9 ablation would result in reduced CSPG expression after spinal cord injury and that this would lead to increased neuroplasticity and improved locomotor recovery. Control and Sox9 conditional knock-out mice were subject to a 70 kdyne contusion spinal cord injury at thoracic level 9. One week after injury, Sox9 conditional knock-out mice expressed reduced levels of CSPG biosynthetic enzymes (Xt-1 and C4st), CSPG core proteins (brevican, neurocan, and aggrecan), collagens 2a1 and 4a1, and Gfap, a marker of astrocyte activation, in the injured spinal cord compared with controls. These changes in gene expression were accompanied by improved hind limb function and locomotor recovery as evaluated by the Basso Mouse Scale (BMS) and rodent activity boxes. Histological assessments confirmed reduced CSPG deposition and collagenous scarring at the lesion of Sox9 conditional knock-out mice, and demonstrated increased neurofilament-positive fibers in the lesion penumbra and increased serotonin immunoreactivity caudal to the site of injury. These results suggest that SOX9 inhibition is a potential strategy for the treatment of SCI.

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“…They are typically enhanced in regions of BBB breakdown (Fitch and Silver, 1997a;Rhodes, et al, 2006), but new evidence also suggests they are upregulated in the perineuronal net in areas distant from the lesion in synaptic centers denervated by the injury (Massey, et al, 2006). In order to appropriately manipulate the extracellular matrix, we must first consider those triggers that initiate the increased production of inhibitory molecules.…”

Section: Triggers For the Production Of Inhibitory Extracellular Matrixmentioning

confidence: 99%

“…While the specific triggers remain unclear, there are a number of hypotheses about factors that contribute to astrocyte activation and gliosis. Degeneration of severed axon tracts appears to lead to gliosis, even in regions remote from the site of trauma in the brain or spinal cord (Barrett et al, 1981;Fitch and Silver, 1997a;Massey, et al, 2006;Murray et al, 1990;Steward and Trimmer, 1997). Cytokines or other molecules that may trigger gliosis include TNF-alpha (Rostworowski et al, 1997), endothelin-1 (Hama et al, 1997), IL-1 (Giulian and Lachman, 1985), IL-6 (Chiang et al, 1994), thrombin (Nishino et al, 1993), and CNTF (Kahn et al, 1995).…”

Section: Triggers For the Production Of Inhibitory Extracellular Matrixmentioning

confidence: 99%

“…Microglial cells are the resident immune system phagocytic cells within the brain and spinal cord (Kim and de Vellis, 2005), and they also respond rapidly for neural protection or healing after injury (Davalos et al, 2005;Wu et al, 2007b). Astrocytes are important for neurotransmitter regulation (Schousboe and Westergaarde, 1995), ion homeostasis (Walz, 1989), blood brain barrier maintenance (Wolburg and Risau, 1995), and the production of extracellular matrix molecules destined for the basal lamina and perineuronal net (Ard et al, 1993;Bernstein et al, 1985;Canning et al, 1996;Grierson et al, 1990;Massey et al, 2006;McKeon et al, 1991;SmithThomas et al, 1994;Tom et al, 2004a). After injury, they are also the major cell type responsible for walling off areas of damage to protect the fragile brain tissue from further erosion (Fitch et al, 1999;Myer et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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CNS injury, glial scars, and inflammation: Inhibitory extracellular matrices and regeneration failure

Fitch

Silver

2008

Experimental Neurology

867

657

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Spinal cord and brain injuries lead to complex cellular and molecular interactions within the central nervous system in an attempt to repair the initial tissue damage. Many studies have illustrated the importance of the glial cell response to injury, and the influences of inflammation and wound healing processes on the overall morbidity and permanent disability that result. The abortive attempts of neuronal regeneration after spinal cord injury are influenced by inflammatory cell activation, reactive astrogliosis and the production of both growth promoting and inhibitory extracellular molecules. Despite the historical perspective that the glial scar was a mechanical barrier to regeneration, inhibitory molecules in the forming scar and methods to overcome them have suggested molecular modification strategies to allow neuronal growth and functional regeneration. Unlike myelin associated inhibitory molecules, which remain at largely static levels before and after central nervous system trauma, inhibitory extracellular matrix molecules are dramatically upregulated during the inflammatory stages after injury providing a window of opportunity for the delivery of candidate therapeutic interventions. While high dose methylprednisolone steroid therapy alone has not proved to be the solution to this difficult clinical problem, other strategies for modulating inflammation and changing the make up of inhibitory molecules in the extracellular matrix are providing robust evidence that rehabilitation after spinal cord and brain injury has the potential to significantly change the outcome for what was once thought to be permanent disability.

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Chondroitinase ABC Digestion of the Perineuronal Net Promotes Functional Collateral Sprouting in the Cuneate Nucleus after Cervical Spinal Cord Injury

Cited by 286 publications

References 55 publications

Plasticity After Spinal Cord Injury: Relevance to Recovery and Approaches to Facilitate It

Plasticity After Spinal Cord Injury: Relevance to Recovery and Approaches to Facilitate It

Conditional Sox9 ablation reduces chondroitin sulfate proteoglycan levels and improves motor function following spinal cord injury

CNS injury, glial scars, and inflammation: Inhibitory extracellular matrices and regeneration failure

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