CHAPTER

The extracellular matrix in plasticity and regeneration after CNS injury and neurodegenerative disease

10 James W. Fawcett1

Department of Clinical Neuroscience, John van Geest Centre for Brain Repair, University of Cambridge, Robinson Way, CA, UK 1 Corresponding author: Tel.: +44-1223-331160; Fax: +44-1223-331174, e-mail address: [email protected]

Abstract Chondroitin sulfate proteoglycans (CSPGs) are involved in several processes relevant to recovery of function after CNS damage. They restrict axon regeneration through their presence in glial scar tissue and plasticity through their presence in perineuronal nets (PNNs), affect memory through their effect on dendritic spines, and influence the inflammatory reaction. Much of our knowledge of these CSPG effects comes from digestion of their glycosaminoglycan chains by the enzyme chondroitinase ABC (ChABC). ChABC after spinal cord injury permits some axon regeneration and greatly increases plasticity through increased sprouting and through digestion of PNNs. When combined with appropriate rehabilitation, ChABC treatment can lead to considerable restoration of function. ChABC treatment of the perirhinal cortex greatly increases retention of object recognition memory. When applied to tauopathy animals that model Alzheimer’s disease, ChABC digestion can restore normal object recognition memory. CSPGs in the adult CNS are found throughout the ECM, but 2% is concentrated in PNNs that surround GABAergic parvalbumin interneurons and other neurons. Knockout of the PNN-organizing protein Crtl1 link protein attenuates PNNs and leads to continued plasticity into adulthood, demonstrating that the CSPGs in PNNs are the key components in the control of plasticity. CSPGs act mainly through their sulfated glycosaminoglycan chains. A disulfated CS-E motif in these chains is responsible for binding of Semaphorin 3A to PNNs where it affects ocular dominance plasticity and probably other forms of plasticity. In addition OTX2 binds to CS-E motifs, where it can act on parvalbumin interneurons to maintain the PNNs.

Keywords extracellular matrix, proteoglycan, chondroitin sulfate proteoglycan, Semaphorin, chondroitinase, plasticity, ocular dominance, axon regeneration, spinal cord Progress in Brain Research, Volume 218, ISSN 0079-6123, http://dx.doi.org/10.1016/bs.pbr.2015.02.001 © 2015 Elsevier B.V. All rights reserved.

213

214

CHAPTER 10 The ECM in plasticity and regeneration

1 PROMOTING CNS PLASTICITY AND REHABILITATION The connection between the extracellular matrix (ECM) and the control of plasticity was first made when it became clear that injection of chondroitinase ABC (ChABC) into the injured spinal cord could affect functional recovery in a way that suggested a rapid promotion of plasticity (Bradbury et al., 2002). The ability of ChABC to promote CNS plasticity in the adult CNS was soon confirmed in various other models, including ocular dominance plasticity (Pizzorusso et al., 2002), sensory axon plasticity in the medullary sensory nuclei (Massey et al., 2006), and other examples. In all these systems, plasticity is characterized by a critical period of enhanced plasticity in the postnatal period, during which newly made projections are refined and optimized. After this there is critical period closure, leading to the adult pattern of plasticity (Bavelier et al., 2010). In adults, there is sufficient plasticity to allow for various forms of memory and behavioral adaptation, but plasticity of the type that allows bypassing of CNS damage is very limited. This has important practical consequences: adults following stroke, traumatic brain injury, and other forms of damage often show limited recovery of function, and rehabilitation may have limited efficacy. On the other hand, children can show very different recovery patterns, depending on the time of injury. In the early years, injuries occur in a nervous system that is still developing and forming connections, and this leads to various and often severe developmental problems (Forsyth et al., 2010). Children injured around the time of critical periods can show a very different recovery pattern to adults, consistent with a higher level of plasticity (Kolb and Gibb, 2007). However, this recovery tends to emphasize sensorimotor recovery, which can be remarkable, but it can be at the expense of cognitive function, leading to children with remarkably normal motor function who fall behind at school and have problems in later life (Forsyth, 2010). ChABC and anti-NogoA are two treatments that have shown consistent efficacy at promoting recovery in animal models of spinal cord injury, repeated in several laboratories and models (Bartus et al., 2012; Cregg et al., 2014; Fawcett et al., 2012; Kwok et al., 2014). Early work focused on the ability of these treatments to enhance axon regeneration, and both treatments, given at the time of injury, allowed some axons of the corticospinal tract to regenerate around the injury site and on into the distal cord for a few millimeters. These regenerated axons, although few in number and short in length, are probably functionally significant. The effectiveness of regenerating axons was shown definitively in an experiment in which axons were enabled to regenerate through a nerve graft with ChABC treatment at the interface between the graft and the host spinal cord; animals recovered forelimb movement but when the graft and the regenerated axons were subsequently cut, the behavioral recovery was lost (Houle et al., 2006). However, it has become clear in recent years that the main action of these treatments is to promote plasticity, enabling the formation of bypass circuits. These circuits can form due to sprouting of damaged axons above the injury, of undamaged axons above and below the injury and due to changes in synaptic strength. Together, these changes allow bypass circuits to form through interneurons and propriospinal connections (Filli et al., 2014; Soleman et al., 2013;

1 Promoting CNS plasticity and rehabilitation

Willi and Schwab, 2013). Enhanced plasticity in the spinal cord can also aid recovery from cortical strokes, which affect the corticospinal neurons that project to the spinal cord (Gherardini et al., 2013; Lindau et al., 2014; Soleman et al., 2012). Recovery of function has been seen not only after the treatment of the perilesional brain region but also after the treatment of the spinal cord. Enhancement of plasticity in the projection region of affected pathways, in this case the corticospinal tract is a logical treatment alternative, allowing the remaining axons projecting to the spinal cord to take over the lost functions. After ChABC treatment of spinal cord injuries, extensive sprouting from the injured and preserved corticospinal tract can be seen in the treated region, with an increase in corticospinal synapses in spinal cord gray matter (Wang et al., 2011; Zhao et al., 2013). While the new circuits formed in this way may not be normal, in that they do not exist in the normal cord, they are clearly capable of restoring function. Recovery after ChABC has yet another mechanism; for reasons not currently understood, some chondroitin sulfate proteoglycans (CSPGs) released following injury are able to block axonal conduction, and digestion with ChABC can restore conduction in various spinal cord pathways (Hunanyan et al., 2010). While treatment with ChABC can restore plasticity to approximately the same level seen during critical periods, this does not automatically lead to restoration of function. There is a general principle that new connections only become useful if you learn how to use them (Mayer et al., 1992); this is one of the bases of rehabilitation after CNS damage. The need to teach animals to use new connections through rehabilitation was shown clearly in experiments in our laboratory in which chondroitinase was given to rats with dorsal column lesions at level C4, and ChABC or control treatment above and below the injury (Garcia-Alias et al., 2009). Without rehabilitation, the treated animals showed no improvement in a corticospinal task, skilled forepaw reaching. Importantly, living in normal animal boxes, rats have no need to use skilled reaching during normal life and they do not therefore rehabilitate themselves in this behavior. However, when given 1 h a day of skilled reaching rehabilitation, ChABC-treated animals now showed remarkable recovery in this task, although rehabilitation was not effective at improving recovery of animals that did not receive ChABC and which therefore had relatively fewer new connections. The experiment also revealed a more worrying aspect of rehabilitation, which is that tasks can be very greedy for the limited resource of new circuits that are formed after injury. Thus, animals that received an hour a day of general environmental enrichment rehabilitation in a cage with ropes, ladders, running wheels completely lost their limited skilled paw reaching ability, while improving at ladder and beam walking. This suggests that behaviors can compete for the limited number of new circuits. ChABC has also been successful at restoring function in cats after spinal cord injury when combined with training at walking over pillars (Tester and Howland, 2008). Findings such as this will certainly have implications if plasticity treatments are combined with rehabilitation. It will be important not only to focus on just one behavior at a time but also to construct a rehabilitation program which includes all the main objectives so that they can compete for the resource of available connections, rather than allow one behavior to seize the available resources unopposed.

215

216

CHAPTER 10 The ECM in plasticity and regeneration

The relative timing of plasticity treatments and rehabilitation has become an important issue with anti-NogoA treatments. The general finding has been that combining rehabilitation and antibody at the same time has led to dysfunctional outcomes, while giving the plasticity treatment first with rehabilitation following later has given a useful boost to recovery (Starkey and Schwab, 2012; Wahl et al., 2014). The reasons for this are not entirely clear, but the pattern of sprouting of preserved axons is different in animals that receive simultaneous treatment rather than sequential. ChABC has improved the results of rehabilitation when both are given at the same time, but experiments varying the relative times of the ChABC and rehabilitation have not been done. Neither ChABC nor anti-NogoA produces a complete recovery of function after spinal cord injury. The question of whether their effects can be additive has recently been addressed. The combination treatment was more effective than either treatment alone, but only if the need to separate anti-NogoA treatment and rehabilitation in time was obeyed. Thus, animals received anti-NogoA treatment shortly after injury, and then after a 1-week delay, rehabilitation was started at the same time as ChABC (Zhao et al., 2013). Critical to the use of treatments for spinal cord injury is timing. Immediately after injury, the clinical program for patients is very intense and it is difficult to include a reconstructive treatment. The logical time to begin a plasticity treatment would be around the time of the beginning of the rehabilitation program, which is usually 3–4 weeks after injury. The effectiveness of anti-NogoA treatment is greatest if it is given soon after injury, and in a recent clinical trial the cut-off was 1 month after injury. ChABC is effective when given soon after injury, but it appears to have a prolonged therapeutic window. Rats whose ChABC and rehabilitation began 1 month after injury showed recovery almost as complete as is seen after acute treatment (Wang et al., 2011). Recent experiments using ChABC for treatment of high spinal injury have shown recovery of respiratory function when the treatment was given 1 year after injury (Sharma et al., 2012). In summary, treatment of experimental spinal cord injury in rodents and cats with ChABC has produced robust functional recovery. The main effect appears to be through stimulation of plasticity, and this opens a window during which rehabilitation can be more effective than normal. The timing of treatment is not critical, and it would certainly be feasible to treat patients at the time of their rehabilitation treatment. The main difficulty with taking ChABC to the clinic has been the need to inject it intraparenchymally. However, there is now experience of injecting multiple large deposits of cells into the injured spinal cord of human patients, and this has not caused problems. It would therefore certainly be feasible to take ChABC to trials in human patients.

2 PLASTICITY, MEMORY, AND ALZHEIMER’S DISEASE Memory is a form of plasticity, and it was therefore possible that a plasticityinducing treatment such as ChABC might have an effect on memory. This was tested using object recognition memory as the memory task. This form of memory, which

2 Plasticity, memory, and Alzheimer’s disease

tests how long a rodent can remember an object before it perceives it again as novel, relies on the function of the perirhinal cortex. The memory effect of ChABC injected into this brain region was unexpected, because one might expect increased plasticity to cause faster forgetting. After ChABC treatment, memory acquisition was normal, but memory retention was very much prolonged. Normally mice will remember and object to which they have been exposed for 5 min as novel for around 12 h, but after ChABC digestion of both perirhinal cortices the memory was retained for around 96 h (Romberg et al., 2013). The mechanism by which this happens is slightly understood; ChABC treatment of perirhinal cortex increased LTD and the stimulus/response ratio, suggesting an increased number and plasticity of connections (Romberg et al., 2013). This plasticity of connections can be seen directly if dendritic spines are studied in hippocampal slices or cortex, where their motility is enhanced by ChABC digestion (de Vivo et al., 2013; Orlando et al., 2012). The mechanism also involves perineuronal nets (PNNs) that surround parvalbumin (PV) interneurons (see more below). Memory acquisition is associated with an increase in the number of inhibitory synapses impinging on PV interneurons, which in turn decreases their production of GABA and thereby increases cortical excitability. ChABC treatment has a similar effect by increasing the number of inhibitory interneurons associated with PV interneurons (Donato et al., 2013). Very long memory persistence of this type might not be particularly useful to normal people; it is important to be able to forget nonimportant information. However, an improvement in memory would be hugely important to those with memory loss due to neurodegenerative disease. In a diffuse neurodegenerative pathology, the effects of ChABC might in theory be beneficial both through a direct effect on spine plasticity and on the secretion of GABA by PV interneurons and the alteration in cortical excitability that comes from this, and through the formation of new circuits and connections, making it possible for the nervous system to adjust local circuitry to compensate for the malfunction of neurons affected by the condition. Two models that represent aspects of Alzheimer’s disease have been used to test for memory restoration by ChABC. Intracellular neuronal damage in Alzheimer’s is associated with the accumulation of hyperphosphorylated tau filaments. A similar accumulation is seen in humans that have various mutations of the tau gene, leading to inherited tauopathies (Ingram and Spillantini, 2002). Mice that express one of these mutant genes, P301S tau, show neuronal pathology that is very similar to the late stages of Alzheimer’s disease, with misshapen neuronal processes, synapse loss, filamentous hyperphosphorylated tau, and eventually neuronal death (Allen et al., 2002). Animals expressing this transgene were tested for retention of novel object memory, and by 3 months they showed complete loss of memory at 1 or 3 h after exposure, although they were able to distinguish novel from familiar objects at short time points. Interestingly, there is little neuronal death at this age, so the loss of function is caused by neuronal malfunction rather than death. At 3 months of age, animals received ChABC to both perirhinal cortices. This completely restored object memory at 1 and 3 h after exposure (Fig. 1). However, this functional restoration was not permanent. Memory declined on roughly the same timescale as restoration of PNNs

217

40cm

40cm

NOR; 3 h retention 0.5

Control P301S

NOR ratio

0.4

§

**

0.3 0.2 0.1 0

1M

3M

P-nase

0.5

ChABC

0.4

NOR ratio

2M Age of animals

** *

** *

0.3 0.2 0.1 0

Control

P301S

0.4

NOR ratio

P-nase 0.3

ChABC

n.s

0.2 0.1 0

Control

P301SHet

FIGURE 1 The object recognition task is shown in the upper picture. Animals explore novel objects for longer periods than familiar objects, so the time spent interacting with each object gives a readout of whether animals remember and object. The middle graph shows that P301 tauopathy transgenics show a progressive loss of object memory, which is lost for 3 h retention by 3 months of age. The lower graphs show that chondroitinase treatment to the perirhinal cortex is able to restore memory in both homo- and heterozygote transgenics.

3 How do chondroitin sulfate proteoglycans control plasticity?

in the ECM, and by 5 weeks after ChABC injection animals had completely lost their ability to remember novel objects at 1 and 3 h after exposure. The amyloid pathology in Alzheimer’s disease can be reproduced in animals with mutations in the APP gene, and these animals develop plaques containing Abeta and show behavioral deficits, including some memory deficits. Injection of ChABC into the hippocampus of APP mutant animals was able to restore contextual memory and LTP (Vegh et al., 2014). In two Alzheimer models, therefore, ChABC injection was able to restore two different types of memory. The conclusion is that ECM modification might be a useful treatment for patients with neurodegenerative disease. It would not alter the gradual progression of disease, but at present there are no successful treatments that can do this. However, the onset of memory loss and other symptoms might be considerably delayed by matrix modification. Because of the age structure of Alzheimer’s, a delay of symptom onset for a few years would greatly reduce the incidence of the condition. However, ChABC is clearly not the correct treatment for Alzheimer’s. It would be impossible to make multiple injections to treat the whole brain, particularly since the injection would have to be repeated every few weeks. This makes it important to understand how the ECM controls memory and plasticity, and to devise alternative treatments that would have the same effects as ChABC while being better pharmaceuticals.

3 HOW DO CHONDROITIN SULFATE PROTEOGLYCANS CONTROL PLASTICITY? The key that has unlocked our understanding of the role of the ECM in CNS plasticity has been the enzyme ChABC. The action of this enzyme is as an endolyase, digesting the sulfated glycosaminoglycan (GAG) chains of CSPGs. These are digested in disaccharides which will diffuse away, leaving the CSPG protein core with four-sugar adaptor sugar chains still attached. Much of the inhibitory activity of CSPGs on axon growth and synapse dynamics and much of the ability to CSPGs to bind to potential effectors is reliant on the GAG chains, so ChABC treatment removes much of the biological effect of the CSPGs. However, there is some evidence that the remaining adaptor chains also have some inhibitory activity (Sharma et al., 2012). It is not only ChABC that affects plasticity and regeneration; knockdown of GAG synthesis using DNA enzymes and siRNAs that target synthesis enzymes can have the same effect (Grimpe and Silver, 2004; Laabs et al., 2007). Since these interventions have effects on GAG chains, but via a different mechanism, the conclusion is that it must be the GAG chains of CSPGs that are predominantly responsible for ECM control of plasticity and memory. The binding properties of GAG chains are determined by the type and pattern of sulfation along the chain, which can create charge structures that have rather specific binding affinities. CS GAG can be sulfated at the 4 and 6 positions and disulfated at the 2,6 and 4,6 positions (Sugahara et al., 2003). The main developmental change is a progressive increase in 4-sulfation and decrease in 6-sulfation (Carulli et al., 2010;

219

220

CHAPTER 10 The ECM in plasticity and regeneration

Kitagawa et al., 1997). Much of this change occurs prenatally, but there is a further change after the end of critical periods. After CNS injury, there is an overall increase in CSPG, with increased sulfation (Properzi et al., 2005). It appears that 4 sulfated forms are particularly inhibitory while 6-sulfated GAG is relatively permissive (Wang et al., 2008). Animals lacking the main enzyme for 6-sulfation are particularly poor regenerators and have very low plasticity (Lin et al., 2011), while 4-sulfated GAG is highly inhibitory to axon growth which can be partly overcome by 6-sulfated GAG. The disulfated GAGs are only around 3% of the total, but 4.6 sulfated CS-E has a large effect on the ability of GAGs to bind to several molecules, so this motif may form part of the binding motif on many inhibitory CSPGs. Staining brain or spinal cord tissue with antibodies or lectins that bind to CSPG core proteins or GAG chains reveals an overall level of staining in the general ECM that surrounds all cells in the CNS. In addition, there are structures that stain much more intensely that surround some classes of neuron, particularly PV + ve GABAergic inhibitory interneurons (Kwok et al., 2011). These are the fast-firing interneurons that play an important role in controlling cortical excitability, and whose maturation and action is critical to the initiation and termination of critical periods (Takesian and Hensch, 2013). The combined observations that ChABC digestion could reactivate plasticity and that concentrations of CSPG are seen around the PV + ve neurons that control plasticity led the hypothesis that these ECM concentrations, known as PNNs, might play a part in the closure of critical periods (Pizzorusso et al., 2002). The structure of PNNs was worked out, demonstrating a composition similar to cartilage (Carulli et al., 2006, 2007). The backbone of the PNN matrix is hyaluronan, long unsulfated chains of repeating disaccharide produced by enzymes of the hyaluronan synthase family. These enzymes are found mostly in the neurons that have PNNs. Many CSPGs have at one end a link domain which binds to hyaluronan. However, this binding is weak and unstable, and in cartilage it has to be stabilized by link proteins. In PNNs two link proteins, Crtl1 and Bral2, are present, and it is these components of PNNs that are upregulated just as the PNNs form (Bekku et al., 2012; Carulli et al., 2010). The other end of CSPGs often contains a domain that binds to tenascin-R, which is also a PNN component. Together these molecules form the condensed and highly stable ternary structure that is the PNN. Indeed, it is so stable that it can only be dissolved in 6 M urea, similarly to cartilage (Deepa et al., 2006). HEK cells transfected to produce hyaluronan synthase and Crtl1 link protein will incorporate their own CSPG, aggrecan, into a matrix structure that is very similar to PNNs (Kwok et al., 2010). PNNs do not have all the same structure. The various CSPGs such as neurocan, versican, and phosphacan are found in a subset of PNNs, while all contain aggrecan, and some (particularly those around PV + ve neurons) stain with wisteria lectin, while others (around pyramidal neurons) do not, some contain Crtl1 link protein, some Bral2, some both. This significance of this PNN language is not understood. The finding that link proteins are upregulated at the time of formation of PNNs suggested that animals lacking these molecules might also lack PNNs. Cortical neurons mostly contain Crtl1, so animals lacking this molecule in the CNS were examined, and found to have greatly attenuated PNNs (Carulli et al., 2010). This finally made it possible to ask whether PNNs are the

3 How do chondroitin sulfate proteoglycans control plasticity?

structures that control plasticity. The effect of ChABC is on all the CSPGs in the CNS, while only 2% are in PNNs. Crtl1 knockouts have the same CSPGs in the CNS as normal animals, but none are concentrated in PNNs. These animals therefore make it possible to ask whether it is specifically CSPGs in PNNs that control plasticity. The Crtl1 knockout animals had continuing ocular dominance plasticity, continuing cuneate nucleus plasticity and also had the same long-term memory persistence as animals treated with ChABC, confirming that CSPGs in PNNs are responsible for the ECM control of plasticity. Also responsible for the formation of PNNs is the diffusible transcription factor OTX2, produced in the visual system and by the choroid plexus. Again interference with OTX actions inhibits PNN formation, and affects the onset and termination of critical periods (Beurdeley et al., 2012). Putting together the effects of ChABC, Crtl1 knockouts, and the OTX2 results, the conclusion is that it is the CS GAG chains in PNNs that are primarily responsible for the control of plasticity by the ECM. However, ChABC delivery by viral vector to the spinal cord also revealed another unexpected effect of GAG digestion. After CNS injury there is a profuse microglial response, with many of the reactive cells showing the M1 phenotype associated with cell damage. After ChABC treatment, many of the microglia instead expressed the markers of the M2 phenotype which is more associated with regeneration and healing (Bartus et al., 2014). If PNNs are the critical structures for the control of plasticity, how do they perform this role? Proteoglycans can act in two main ways. First, they can act directly on receptors, and inhibitory effects of CSPGs can be mediated via the PTPsigma receptor (Shen et al., 2009). Second, they frequently act by sequestering active molecules to particular places and introducing them to receptors. Two molecules suggest that the sequestering role can be important. First OTX2, described above, binds to CS-E motifs in the CSPGs of PNNs, bringing OTX2 to PV + ve interneurons and ensuring that they continue in the mature state with mature PNNs (Beurdeley et al., 2012). Second, the guidance molecule Semaphorin 3A (Sema3A) is produced by many neurons in the adult CNS, and its plexin and neuropilin receptors are also widely present. However, staining of brain with antibodies to Sema3A reveals that almost all of it is associated with PNNs. This molecule also binds particularly to CS-E motifs on the CS GAG chains (Dick et al., 2013; Vo et al., 2013). Sema3A has strong effects on synapse dynamics in vitro, so its effects on plasticity in vivo have recently been tested. Using Fc-neuropilin receptor bodies as blockers of Sema3A–neuropilin interactions, it has been found that expression of the blocking receptor bodies in the adult visual cortex can reactivate ocular dominance plasticity in adult rats (Pizzorusso, unpublished results). It is probable that more of the molecules that guide axons during development will be found to bind to PNNs in the adult CNS and to have effects on synapse dynamics. What might PNNs do to synapses? First, they have an effect on dendritic spines, restraining dendritic morphological changes. Digestion with ChABC transforms spines into “search” mode, where they produce motile filopodia (de Vivo et al., 2013; Orlando et al., 2012). Second, digestion of PNNs increases the number of inhibitory synapses on PV + ve interneurons, affecting their production of GABA and thereby decreasing cortical inhibition and increasing cortical excitability (Donato et al., 2013).

221

222

CHAPTER 10 The ECM in plasticity and regeneration

4 FUTURE DIRECTIONS It is clear from the many experiments that have examined functional recovery after many different types of CNS lesion and degeneration that reactivation of plasticity by modification of the ECM and by treatment with anti-NogoA can enable functional recovery, particularly when combined with rehabilitation. It is unfortunate that ChABC has not yet entered clinical trials, because there is a good probability that patients would benefit from its use. The main problem has been the need to inject ChABC directly into the brain or spinal cord parenchyma, following which it will diffuse and digest for around 0.5 cm, creating a 1-cm region of treatment. After a single injection, some active enzyme can be found for up to 3 weeks, following which the ECM will start to reconstruct and plasticity will revert to the adult pattern (Lin et al., 2008). In a small structure, such as the human spinal cord, a few injections would give complete digestion around the region of an injury, and 5 weeks of enhanced plasticity would be long enough to achieve some intense physiotherapy. There has been some resistance to the idea of making injections into the injured spinal cord, but recent experience with injecting cell deposits has shown that injections of substantial volumes can be made without collateral damage. ChABC needs, therefore, to enter clinical trials as soon as possible. However, while ChABC treatment is feasible for spinal cord injury or enhancing spinal cord plasticity for stroke, it is not a practicable treatment for neurodegenerative disease where the entire brain is the target. For these conditions, another form of treatment that targets the ECM and the PNN is needed. Antibodies that block Sema3A binding to PNNs, peptides that block OTX2 and Sema3A binding, inhibitors of sulfotransferase enzymes, and other potential therapeutics are under development. It should be easier to use these for the treatment of human patients with lesions and neurodegenerative conditions.

ACKNOWLEDGMENTS This work was supported by grants from the European Research Council, the Medical Research Council, and the Christopher and Dana Reeve Foundation.

CONFLICT OF INTEREST J. F. is a paid consultant for Acorda Therapeutics and Vertex Pharmaceuticals.

REFERENCES Allen, B., Ingram, E., Takao, M., Smith, M.J., Jakes, R., Virdee, K., Yoshida, H., Holzer, M., Craxton, M., Emson, P.C., Atzori, C., Migheli, A., Crowther, R.A., Ghetti, B., Spillantini, M.G., Goedert, M., 2002. Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein. J. Neurosci. 22, 9340–9351.

References

Bartus, K., James, N.D., Bosch, K.D., Bradbury, E.J., 2012. Chondroitin sulphate proteoglycans: key modulators of spinal cord and brain plasticity. Exp. Neurol. 235, 5–17. Bartus, K., James, N.D., Didangelos, A., Bosch, K.D., Verhaagen, J., Yanez-Munoz, R.J., Rogers, J.H., Schneider, B.L., Muir, E.M., Bradbury, E.J., 2014. Large-scale chondroitin sulfate proteoglycan digestion with chondroitinase gene therapy leads to reduced pathology and modulates macrophage phenotype following spinal cord contusion injury. J. Neurosci. 34, 4822–4836. Bavelier, D., Levi, D.M., Li, R.W., Dan, Y., Hensch, T.K., 2010. Removing brakes on adult brain plasticity: from molecular to behavioral interventions. J. Neurosci. 30, 14964–14971. Bekku, Y., Saito, M., Moser, M., Fuchigami, M., Maehara, A., Nakayama, M., Kusachi, S., Ninomiya, Y., Oohashi, T., 2012. Bral2 is indispensable for the proper localization of brevican and the structural integrity of the perineuronal net in the brainstem and cerebellum. J. Comp. Neurol. 520, 1721–1736. Beurdeley, M., Spatazza, J., Lee, H.H., Sugiyama, S., Bernard, C., Di Nardo, A.A., Hensch, T.K., Prochiantz, A., 2012. Otx2 binding to perineuronal nets persistently regulates plasticity in the mature visual cortex. J. Neurosci. 32, 9429–9437. Bradbury, E.J., Moon, L.D.F., Popat, R.J., King, V.R., Bennett, G.S., Patel, P.N., Fawcett, J.W., McMahon, S.B., 2002. Chondroitinase ABC promotes axon regeneration and functional recovery following spinal cord injury. Nature 416, 636–640. Carulli, D., Rhodes, K.E., Brown, D.J., Bonnert, T.P., Pollack, S.J., Oliver, K., Strata, P., Fawcett, J.W., 2006. The composition of perineuronal nets in the adult rat cerebellum and the cellular origin of their components. J. Comp. Neurol. 494, 559–577. Carulli, D., Deepa, S.S., Fawcett, J.W., 2007. Upregulation of aggrecan, link protein 1 and hyaluronan synthases during formation of perineuronal nets in the rat cerebellum. J. Comp. Neurol. 501, 83–94. Carulli, D., Pizzorusso, T., Kwok, J.C., Putignano, E., Poli, A., Forostyak, S., Andrews, M.R., Deepa, S.S., Glant, T., Fawcett, J.W., 2010. Animals lacking link protein have attenuated perineuronal nets and persistent plasticity. Brain 133, 2331–2347. Cregg, J.M., DePaul, M.A., Filous, A.R., Lang, B.T., Tran, A., Silver, J., 2014. Functional regeneration beyond the glial scar. Exp. Neurol. 253, 197–207. de Vivo, L., Landi, S., Panniello, M., Baroncelli, L., Chierzi, S., Mariotti, L., Spolidoro, M., Pizzorusso, T., Maffei, L., Ratto, G.M., 2013. Extracellular matrix inhibits structural and functional plasticity of dendritic spines in the adult visual cortex. Nat. Commun. 4, 1484. Deepa, S.S., Carulli, D., Galtrey, C., Rhodes, K., Fukuda, J., Mikami, T., Sugahara, K., Fawcett, J.W., 2006. Composition of perineuronal net extracellular matrix in rat brain: a different disaccharide composition for the net-associated proteoglycans. J. Biol. Chem. 281, 17789–17800. Dick, G., Tan, C.L., Alves, J.N., Ehlert, E.M., Miller, G.M., Hsieh-Wilson, L.C., Sugahara, K., Oosterhof, A., van Kuppevelt, T.H., Verhaagen, J., Fawcett, J.W., Kwok, J.C., 2013. Semaphorin 3A binds to the perineuronal nets via chondroitin sulfate type E motifs in rodent brains. J. Biol. Chem. 288, 27384–27395. Donato, F., Rompani, S.B., Caroni, P., 2013. Parvalbumin-expressing basket-cell network plasticity induced by experience regulates adult learning. Nature 504, 272–276. Fawcett, J.W., Schwab, M.E., Montani, L., Brazda, N., Muller, H.-W., 2012. Defeating inhibition of regeneration by scar and myelin components. In: Verhaagen, J., McDonald, J.W. (Eds.), Handbook of Clinical Neurology. Elsevier, Amsterdam.

223

224

CHAPTER 10 The ECM in plasticity and regeneration

Filli, L., Engmann, A.K., Zorner, B., Weinmann, O., Moraitis, T., Gullo, M., Kasper, H., Schneider, R., Schwab, M.E., 2014. Bridging the gap: a reticulo-propriospinal detour bypassing an incomplete spinal cord injury. J. Neurosci. 34, 13399–13410. Forsyth, R.J., 2010. Back to the future: rehabilitation of children after brain injury. Arch. Dis. Child. 95, 554–559. Forsyth, R.J., Salorio, C.F., Christensen, J.R., 2010. Modelling early recovery patterns after paediatric traumatic brain injury. Arch. Dis. Child. 95, 266–270. Garcia-Alias, G., Barkhuysen, S., Buckle, M., Fawcett, J.W., 2009. Chondroitinase ABC treatment opens a window of opportunity for task-specific rehabilitation. Nat. Neurosci. 12, 1145–1151. Gherardini, L., Gennaro, M., Pizzorusso, T., 2013. Perilesional treatment with chondroitinase ABC and motor training promote functional recovery after stroke in rats. Cereb. Cortex 25, 202–212. Grimpe, B., Silver, J., 2004. A novel DNA enzyme reduces glycosaminoglycan chains in the glial scar and allows microtransplanted dorsal root ganglia axons to regenerate beyond lesions in the spinal cord. J. Neurosci. 24, 1393–1397. Houle, J.D., Tom, V.J., Mayes, D., Wagoner, G., Phillips, N., Silver, J., 2006. Combining an autologous peripheral nervous system “bridge” and matrix modification by chondroitinase allows robust, functional regeneration beyond a hemisection lesion of the adult rat spinal cord. J. Neurosci. 26, 7405–7415. Hunanyan, A.S., Garcia-Alias, G., Alessi, V., Levine, J.M., Fawcett, J.W., Mendell, L.M., Arvanian, V.L., 2010. Role of chondroitin sulfate proteoglycans in axonal conduction in mammalian spinal cord. J. Neurosci. 30, 7761–7769. Ingram, E.M., Spillantini, M.G., 2002. Tau gene mutations: dissecting the pathogenesis of FTDP-17. Trends Mol. Med. 8, 555–562. Kitagawa, H., Tsutsumi, K., Tone, Y., Sugahara, K., 1997. Developmental regulation of the sulfation profile of chondroitin sulfate chains in the chicken embryo brain. J. Biol. Chem. 272, 31377–31381. Kolb, B., Gibb, R., 2007. Brain plasticity and recovery from early cortical injury. Dev. Psychobiol. 49, 107–118. Kwok, J.C., Carulli, D., Fawcett, J.W., 2010. In vitro modeling of perineuronal nets: hyaluronan synthase and link protein are necessary for their formation and integrity. J. Neurochem. 114, 1447–1459. Kwok, J.C., Dick, G., Wang, D., Fawcett, J.W., 2011. Extracellular matrix and perineuronal nets in CNS repair. Dev. Neurobiol. 71, 1073–1089. Kwok, J.C., Heller, J.P., Zhao, R.R., Fawcett, J.W., 2014. Targeting inhibitory chondroitin sulphate proteoglycans to promote plasticity after injury. Methods Mol. Biol. 1162, 127–138. Laabs, T.L., Wang, H., Katagiri, Y., McCann, T., Fawcett, J.W., Geller, H.M., 2007. Inhibiting glycosaminoglycan chain polymerization decreases the inhibitory activity of astrocytederived chondroitin sulfate proteoglycans. J. Neurosci. 27, 14494–14501. Lin, R., Kwok, J.C., Crespo, D., Fawcett, J.W., 2008. Chondroitinase ABC has a long lasting effect on chondroitin sulphate glycosaminoglycan content in the injured rat brain. J. Neurochem. 104, 400–408. Lin, R., Rosahl, T.W., Whiting, P.J., Fawcett, J.W., Kwok, J.C., 2011. 6-Sulphated chondroitins have a positive influence on axonal regeneration. PLoS One 6, e21499. Lindau, N.T., Banninger, B.J., Gullo, M., Good, N.A., Bachmann, L.C., Starkey, M.L., Schwab, M.E., 2014. Rewiring of the corticospinal tract in the adult rat after unilateral stroke and anti-Nogo-A therapy. Brain 137, 739–756.

References

Massey, J.M., Hubscher, C.H., Wagoner, M.R., Decker, J.A., Amps, J., Silver, J., Onifer, S.M., 2006. Chondroitinase ABC digestion of the perineuronal net promotes functional collateral sprouting in the cuneate nucleus after cervical spinal cord injury. J. Neurosci. 26, 4406–4414. Mayer, E., Brown, V.J., Dunnett, S.B., Robbins, T.W., 1992. Striatal graft-associated recovery of a lesion-induced performance deficit in the rat requires learning to use the transplant. Eur. J. Neurosci. 4, 119–126. Orlando, C., Ster, J., Gerber, U., Fawcett, J.W., Raineteau, O., 2012. Peridendritic chondroitin sulfate proteoglycans restrict structural plasticity in an integrin-dependent manner. J. Neurosci. 32, 18009–18017. Pizzorusso, T., Medini, P., Berardi, N., Chierzi, S., Fawcett, J.W., Maffei, L., 2002. Reactivation of ocular dominance plasticity in the adult visual cortex with chondroitinase ABC. Science 298, 1248–1251. Properzi, F., Carulli, D., Asher, R.A., Muir, E., Camargo, L.M., van Kuppevelt, T.H., ten Dam, G.B., Furukawa, Y., Mikami, T., Sugahara, K., Toida, T., Geller, H.M., Fawcett, J.W., 2005. Chondroitin 6-sulphate synthesis is up-regulated in injured CNS, induced by injury-related cytokines and enhanced in axon-growth inhibitory glia. Eur. J. Neurosci. 21, 378–390. Romberg, C., Yang, S., Melani, R., Andrews, M.R., Horner, A.E., Spillantini, M.G., Bussey, T.J., Fawcett, J.W., Pizzorusso, T., Saksida, L.M., 2013. Depletion of perineuronal nets enhances recognition memory and long-term depression in the perirhinal cortex. J. Neurosci. 33, 7057–7065. Sharma, H., Alilain, W.J., Sadhu, A., Silver, J., 2012. Treatments to restore respiratory function after spinal cord injury and their implications for regeneration, plasticity and adaptation. Exp. Neurol. 235, 18–25. Shen, Y., Tenney, A.P., Busch, S.A., Horn, K.P., Cuascut, F.X., Liu, K., He, Z., Silver, J., Flanagan, J.G., 2009. PTPsigma is a receptor for chondroitin sulfate proteoglycan, an inhibitor of neural regeneration. Science 326, 592–596. Soleman, S., Yip, P.K., Duricki, D.A., Moon, L.D., 2012. Delayed treatment with chondroitinase ABC promotes sensorimotor recovery and plasticity after stroke in aged rats. Brain 135, 1210–1223. Soleman, S., Filippov, M.A., Dityatev, A., Fawcett, J.W., 2013. Targeting the neural extracellular matrix in neurological disorders. Neuroscience 253C, 194–213. Starkey, M.L., Schwab, M.E., 2012. Anti-Nogo-A and training: can one plus one equal three? Exp. Neurol. 235, 53–61. Sugahara, K., Mikami, T., Uyama, T., Mizuguchi, S., Nomura, K., Kitagawa, H., 2003. Recent advances in the structural biology of chondroitin sulfate and dermatan sulfate. Curr. Opin. Struct. Biol. 13, 612–620. Takesian, A.E., Hensch, T.K., 2013. Balancing plasticity/stability across brain development. Prog. Brain Res. 207, 3–34. Tester, N.J., Howland, D.R., 2008. Chondroitinase ABC improves basic and skilled locomotion in spinal cord injured cats. Exp. Neurol. 209, 483–496. Vegh, M.J., Heldring, C.M., Kamphuis, W., Hijazi, S., Timmerman, A.J., Li, K.W., van Niero, P., Mansvelder, H.D., Hol, E.M., Smit, A.B., van Kesteren, R.E., 2014. Reducing hippocampal extracellular matrix reverses early memory deficits in a mouse model of Alzheimer’s disease. Acta Neuropathol. Commun. 2, 76. Vo, T., Carulli, D., Ehlert, E.M., Kwok, J.C., Dick, G., Mecollari, V., Moloney, E.B., Neufeld, G., De, W.F., Fawcett, J.W., Verhaagen, J., 2013. The chemorepulsive axon guidance protein semaphorin 3A is a constituent of perineuronal nets in the adult rodent brain. Mol. Cell. Neurosci. 56, 186–200.

225

226

CHAPTER 10 The ECM in plasticity and regeneration

Wahl, A.S., Omlor, W., Rubio, J.C., Chen, J.L., Zheng, H., Schroter, A., Gullo, M., Weinmann, O., Kobayashi, K., Helmchen, F., Ommer, B., Schwab, M.E., 2014. Neuronal repair. Asynchronous therapy restores motor control by rewiring of the rat corticospinal tract after stroke. Science 344, 1250–1255. Wang, H., Katagiri, Y., McCann, T.E., Unsworth, E., Goldsmith, P., Yu, Z.X., Tan, F., Santiago, L., Mills, E.M., Wang, Y., Symes, A.J., Geller, H.M., 2008. Chondroitin-4sulfation negatively regulates axonal guidance and growth. J. Cell Sci. 121, 3083–3091. Wang, D., Ichiyama, R.M., Zhao, R., Andrews, M.R., Fawcett, J.W., 2011. Chondroitinase combined with rehabilitation promotes recovery of forelimb function in rats with chronic spinal cord injury. J. Neurosci. 31, 9332–9344. Willi, R., Schwab, M.E., 2013. Nogo and Nogo receptor: relevance to schizophrenia? Neurobiol. Dis. 54, 150–157. Zhao, R.R., Andrews, M.R., Wang, D., Warren, P., Gullo, M., Schnell, L., Schwab, M.E., Fawcett, J.W., 2013. Combination treatment with anti-Nogo-A and chondroitinase ABC is more effective than single treatments at enhancing functional recovery after spinal cord injury. Eur. J. Neurosci. 38, 2946–2961.

The extracellular matrix in plasticity and regeneration after CNS injury and neurodegenerative disease.

Chondroitin sulfate proteoglycans (CSPGs) are involved in several processes relevant to recovery of function after CNS damage. They restrict axon rege...
450KB Sizes 0 Downloads 18 Views