The role of chondroitin sulfate proteoglycans in regeneration and plasticity in the central nervous system

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a v a i l a b l e a t w w w. s c i e n c e d i r e c t . c o m

w w w. e l s e v i e r. c o m / l o c a t e / b r a i n r e s r e v

Review

The role of chondroitin sulfate proteoglycans in regeneration and plasticity in the central nervous system Clare M. Galtrey, James W. Fawcett ⁎ Cambridge Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Robinson Way, Cambridge, CB2 2PY, UK

A R T I C LE I N FO

AB S T R A C T

Article history:

Chondroitin sulfate proteoglycans (CSPGs) consist of a core protein and glycosaminoglycan

Accepted 11 September 2006

(GAG) chains. There is enormous structural diversity among CSPGs due to variation in the

Available online 11 January 2007

core protein, the number of GAG chains and the extent and position of sulfation. Most CSPGs are secreted from cells and participate in the formation of the extracellular matrix (ECM).

Keywords:

CSPGs are able to interact with various growth-active molecules and this may be important

Chondroitin sulfate proteoglycans

in their mechanism of action.

Plasticity

In the normal central nervous system (CNS), CSPGs have a role in development and

Central nervous system injury

plasticity during postnatal development and in the adult. Plasticity is greatest in the young,

Perineuronal nets

especially during critical periods. CSPGs are crucial components of perineuronal nets

Chondroitinase

(PNNs). PNNs have a role in closure of the critical period and digestion of PNNs allows their

Axon regeneration

re-opening. In the adult, CSPGs play a part in learning and memory and the hypothalamoneurohypophysial system. CSPGs have an important role in CNS injuries and diseases. After CNS injury, CSPGs are the major inhibitory component of the glial scar. Removal of CSPGs improves axonal regeneration and functional recovery. CSPGs may also be involved in the pathological processes in diseases such as epilepsy, stroke and Alzheimer's disease. Several possible methods of manipulating CSPGs in the CNS have recently been identified. The development of methods to remove CSPGs has considerable therapeutic potential in a number of CNS disorders. © 2006 Elsevier B.V. All rights reserved.

Contents 1. 2.

The structure of chondroitin sulfate proteoglycans . . . . . Chondroitin sulfate proteoglycans, the extracellular matrix 2.1. General structure and organization of the ECM . . . 2.2. The heterogeneity of ECM components in the CNS .

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⁎ Corresponding author. Fax: +44 1223 331174. E-mail address: [email protected] (J.W. Fawcett). Abbreviations: BRAL1, brain link protein 1; BRAL2, brain link protein 2; ChABC, chondroitinase ABC; CRTL1, cartilage link protein 1; CSGAG, chondroitin sulfate glycosaminoglycans; CSPG, chondroitin sulfate proteoglycan; ECM, extracellular matrix; GalNAc, N-acetyl galactosamine; GlcA, glucuronic acid; PNNs, perineuronal nets; RHAMM, receptor for hyaluronic-acid-mediated motility; RPTPβ, phosphacan/receptor-type protein–tyrosine phosphatase β; WFA, Wisteria floribunda agglutinin 0165-0173/$ – see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.brainresrev.2006.09.006

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2.3. The function of ECM in the CNS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Perineuronal Nets-specialized organization of the ECM in the CNS . . . . . . . . . . . . . . . . . . . . . . . . 3. Functions of chondroitin sulfate proteoglycans and plasticity in the adult central nervous system . . . . . . . . . . 3.1. The role of CSPGs in plasticity during postnatal development-ocular dominance plasticity. . . . . . . . . . . 3.2. The role of CSPGs in synaptic plasticity in the adult CNS-learning and memory. . . . . . . . . . . . . . . . . 3.3. The role of CSPGs in structural plasticity in the adult CNS–hypothalamo–neurohypophysial system plasticity 4. Chondroitin sulfate proteoglycans and CNS pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Chondroitin sulfate proteoglycans and traumatic central nervous system injury . . . . . . . . . . . . . . . . 4.1.1. Chondroitin sulfate proteoglycans, central nervous system injury and inhibition of axonal regeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1.2. CSPGs, CNS injury and plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. The role of CSPG in the pathogenesis of CNS disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.1. Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.2. Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2.3. Alzheimer's disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Mechanisms of CSPG regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Therapeutic potential of manipulating CSPGs in the CNS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. The structure of chondroitin sulfate proteoglycans CSPGs consist of a large variety of core proteins and covalently linked chondroitin sulfate glycosaminoglycans (CS-GAGs) (Hartmann and Maurer, 2001). These core proteins are mostly molecules composed of multiple domains that affect their integration into the ECM or provide putative attachment or signaling functions (Fig. 1). The four major groups of CSPGs are (1) lecticans (a family including aggrecan, versican, neurocan, brevican) (Yamaguchi, 2000); (2) phosphacan/receptor-type protein–tyrosine phosphatase β (RPTPβ) (Maurel et al., 1994; Garwood et al., 2003); (3) small leucine-rich proteoglycans (e.g., decorin and biglycan) (Hocking et al., 1998); (4) other CSPGs including neuroglycan-C (Oohira et al., 2004); and NG2 (Stallcup, 2002). CS-GAGs are long, linear chains that are formed by repeating disaccharide units (Brooks et al., 2002). The basic disaccharide unit of chondroitin sulfate is a glucuronic acid (GlcA) linked via a β-glycosidic bond to N-acetyl galactosamine (GalNAc). GAG chains are linked to serine residues in core proteins via xylose by the enzyme xylosyltransferase. After xylose addition, a linkage tetrasaccharide is generated followed by addition of β-GalNAc (Prydz and Dalen, 2000). The disaccharides are polymerized into long chains by the recently identified human chondroitin synthase (Kitagawa et al., 2001) and the protein chondroitin polymerizing factor (Kitagawa et al., 2003). These CS-GAGs are then modified by sulfation and the positions of sulfation define the type of CS (Properzi et al., 2003). CS disaccharides can be monosulfated in the 4 or 6 position of the GalNAc residue (CS-A and CS-C, respectively) or disulfated in the 2 and 6 position of the GlcA and GAlNAc, respectively (CS-D), and in the 4 and 6 position of the GalNAc (CS-E) (Sugahara et al., 2003) (Fig. 2). The enzymes responsible for these sulfation patterns are the chondroitin sulfotransferases (CSSTs). The CSSTs known to date are three isoforms of chondroitin 4-sulfotransferase, two isoforms of chondroitin 6-

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sulfotransferase, uronyl-2-sulfotransferase and N-acetylgalactosamine 4-sulfate 6-O-sulfotransferase (Habuchi, 2000). The sulfation of the GAG chains in specific positions and patterns affects their ability to bind other molecules. There is considerable variation in the number of GAG chains that attach to the core proteins. Some CSPGs contain only one GAG chain (e.g., decorin), whereas others have more than 100 chains (e.g., aggrecan) (Fig. 1). CSPGs are either secreted into the ECM or inserted into the plasma membrane (Fig. 1) (Matsui and Oohira, 2004). Matrix CSPGs include the lecticans, phosphacan and the small leucine-rich proteoglycans. The membrane CSPGs either have type I orientations with a single membranespanning domain (e.g., NG2, neuroglycan-C) or a GPI anchor (GPI-brevican). The CSPGs present in the ECM of the CNS are the focus of this review.

2. Chondroitin sulfate proteoglycans, the extracellular matrix and perineuronal nets 2.1.

General structure and organization of the ECM

ECM components are secreted locally and assembled in the surrounding extracellular space. The major components of the ECM are (1) GAGs, either bound to proteins, as proteoglycans, or unbound in the form of hyaluronan; (2) fibrous proteins (e.g., collagens and elastin); and (3) adhesive glycoproteins (e.g., fibronectin, laminin and tenascin) and a wide variety of secreted growth factors and other molecules, many of which bind with various affinities to GAGs and other matrix components. ECM is present in all tissues but variations in the relative amounts of the different types of matrix macromolecules and the way in which they are organized gives rise to many diverse forms of ECM, e.g., bone, tendons and cornea (Alberts et al., 2002). The ECM of the CNS is unique in composition and organization as it contains relatively small

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Fig. 1 – Structures of chondroitin sulfate proteoglycans in the central nervous system. (A) Lecticans are a family of CSPGs that have a core protein with globular domains at the N- and C-terminal connected by a central domain that contains attachment sites for CS-GAG chains. All lecticans contain N-terminal G1 domains and C-terminal G3 domains. Only aggrecan contains the G2 domain. The G1 domain consists of an Ig-like loop and two link modules, whereas the G2 domain has two link modules only. The G3 domain contains a C-type lectin domain flanked by EGF-like and complement regulatory protein (CRP)-like domain. The N-terminal globular domain (G1) binds hyaluronan and link protein and the C-terminal globular domain (G3) binds glycolipids and tenascins. (B) Phosphacan/receptor-type protein–tyrosine phosphatase β (RPTPβ) has four alternative spliced variants: (i) full-length form of RPTPβ that has an N-terminal carbonic anhydrase-like domain (CA), a fibronectin type III domain (FN), CS-GAG attachment regions and two intracellular tyrosine phosphatase domains (D1 and D2); (ii) phosphacan, a soluble form that lacks the intracellular tyrosine phosphatase domains; (iii) shorter receptor form of RPTPβ that lacks most of the CS-GAG attachment regions; and (iv) phosphacan short isoform that is not a proteoglycan as it lacks the CS-GAG attachment regions and two phosphatase domain. (C) Small leucine-rich proteoglycans (SLRPs) (e.g., decorin and biglycan) all have core proteins with the leucine-rich repeats which usually occupy more than 70% of the core proteins that are flanked by cysteine-rich clusters that may form disulfide bonds. There are four cysteine residues at the amino terminal region and two cysteine residues at the carboxyl terminal side. (D) Part-time proteoglycans are proteins occur both in a proteoglycan form and in a non-proteoglycan form without sulfated glycosaminoglycans (e.g., neuroglycan-C, thrombomodulin and apican). Neuroglycan-C is a transmembrane glycoprotein with a single EGF module whose expression is restricted in the central nervous system. It exists in a proteoglycan form with a single chondroitin sulfate chain in the developing nervous system, whereas it exists largely in a non-proteoglycan form in the mature nervous system. (E) Other CSPGs, such as NG2, that is a membrane-spanning CSPG that lacks any sequence homology to other PGs. Its ectodomain is composed of two globular domains separated by an extended region in which the GAG chains are attached.

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Fig. 2 – Sulfation of chondroitin sulfate proteoglycans. Glycosaminoglycan chains of chondroitin sulfate (CS-GAG) consist of a repeating disaccharide unit formed by N-acetyl galactosamine (GalNAc) and glucuronate (GlcA). These CS-GAG chains are modified by sulfation and the positions of sulfation define the type of CS. Chondroitin sulfate disaccharides can be sulfated in four different ways. (a) CS-A is monosulfated in the 4 position (position show by grey numbers) of the GalNAc residue, (b) CS-C is monosulfated n the 6 position of the GalNAc residue, (c) CS-D is disulfated in the 2 and 6 position of the GlcA and GalNAc and (d) CS-E is disulfated in the 4 and 6 position of the GalNAc. The enzymes responsible for these modifications are the chondroitin sulfotransferases (CSSTs). CS-A is sulfated by C4ST, CS-C by C6ST. In CS-D, uronyl-2-sulfotransferase (UST) is involved in the 2-sulfation of GlcA and in CS-E GalNAc4S-6ST is involved in sulfating the 6 position.

amounts of fibrous proteins and high amounts of GAGs (Novak and Kaye, 2000) and is organized around certain neurons to produce specialized condensed ECM, known as perineuronal nets (PNNs) (Yamaguchi, 2000). The major components of the ECM in the CNS are (1) hyaluronan, the simplest of the GAGs that lacks a protein core and consists of repeating non-sulfated disaccharide units each composed of glucuronic acid and N-acetylglucosamine to produce chains of up to 25,000 disaccharides in length; (2) CSPGs, primarily the lectican family, which use their core

protein N and C terminal domains to interact with hyaluronan and tenascin respectively (Yamaguchi, 2000); (3) link protein, a small glycoprotein able to bind to hyaluronan and aggrecan (Neame and Barry, 1994); and (4) tenascin, an adhesive molecule related to fibronectin and laminin that exists as dimers or trimers and interacts with CSPGs. The organization of the ECM in the CNS involves the interaction of all the components (Table 1). The lectican family of CSPGs are able to bind to both hyaluronan, via N terminal domain, and to tenascin, via the C terminal domain (Yamaguchi, 2000). The interaction between hyaluronan and CSPGs is stabilized via link protein (Binette et al., 1994). The C-terminal domain of the lecticans interacts with the fibronectin type III domains 3–5 of tenascin-R (Yamaguchi, 2000) and tenascin-C (Day et al., 2004). Biochemical studies show that tenascin-R and tenascin-C interact with different lecticans, e.g., tenascin-C interacts strongly with neurocan but weakly with brevican while tenascin-R interacts most strongly with brevican (Rauch et al., 1997; Aspberg et al., 1997; Day et al., 2004). Phosphacan can also interact with tenascin-R (Milev et al., 1998) and tenascin-C (Milev et al., 1997). Tenascin exists as dimers or trimers. This multimeric nature of tenascin-R molecules results in the formation of an organized lattice of hyaluronan. Electron microscopy has shown that full-length tenascin-R and tenascin-C are able to crosslink hyaluronan–aggrecan complexes (Lundell et al., 2004). The importance of this interaction to the organization of the ECM is seen in immunohistochemical studies of tenascin-R knockout mice in which the ECM structure is disrupted. However, there is probably considerable redundancy amongst ECM molecules because even after the knockout of neurocan, brevican, tenascin-R and tenascin-C there is an ECM: the structure of which is supported by the interaction of fibulin-2 and versican (Rauch et al., 2005). Fibulin-2 is a dimeric glycoprotein that can interact with the C-terminal end of versican, thereby cross-linking two versican molecules (Olin et al., 2001).

2.2.

The heterogeneity of ECM components in the CNS

There are variations to the basic organization of the ECM due to the distinctive distributions of the individual members of the CSPG and link protein families. There are four link proteins cartilage link protein 1 (CRTL1), brain link protein 1 (BRAL1), brain link protein 2 (BRAL2) and link protein 3 (Asher et al., 1995; Hirakawa et al., 2000; Spicer et al., 2003; Bekku et al., 2003). They consist of two hyaluronan-binding link modules and one module of the immunoglobulin type. The different link proteins might have different preferences in supporting the hyaluronan-binding ability of the four lectican proteoglycans. Biochemical studies show that CRTL1 supports the hyaluronan-binding ability of aggrecan and aggrecan is strongly decreased in cartilage of CRTL1 knockout mice (Watanabe and Yamada, 1999) and this phenotype is rescued by expression of CRTL1 (Czipri et al., 2003). However, the result of a lack of CRTL1 in the CNS is not yet described. CRTL1 also supports the hyaluronan-binding ability of neurocan (Rauch et al., 2004). Immunohistochemical studies in mice demonstrate that BRAL 1 colocalizes with versican at the nodes of Ranvier in white matter tracts (Oohashi et al.,

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Table 1 – The molecular interactions of chondroitin sulfate proteoglycans in the extracellular matrix and perineuronal net formation CSPGs

Hyaluronan

Tenascin T-R

Link protein T-C

Lecticans Aggrecan Versican

YES (Yamaguchi, 2000)

YES (Yamaguchi, 2000)

YES (Day et al., 2004)

Neurocan

Brevican

Phosphacan/RPTPβ Phosphacan NO

a b

YES (Milev et al., 1998)

YES (Milev et al., 1997)

CRTL1 YES (Shi et al., 2004) YES (Shi et al., 2004; Matsumoto et al., 2003) YES (Rauch et al., 2004) –

BRAL 1

BRAL 2

–a

–

YES b (Oohashi et al., 2002)

–

–

–

–

YESb (Bekku et al., 2003)

NO

Indicates that there is currently no evidence for an interaction but it is theoretically possible and more evidence is required. Shown by immunohistochemical colocalization only.

2002) while BRAL 2 appears to be mainly associated with brevican (Bekku et al., 2003). Strikingly, all four link protein genes are located immediately adjacent to the four CSPG core protein genes creating four pairs of CSPG-link protein genes within the mammalian genome: CRTL1 with versican, BRAL 1 with brevican and BRAL 2 with neurocan (Spicer et al., 2003). However, the specificity of support of each link protein for the binding of the individual lecticans to hyaluronan appears to be more complex than a simple one-to-one relationship and remains to be elucidated. For example, versican also binds CRTL1 and with a higher affinity than aggrecan (Matsumoto et al., 2003; Shi et al., 2004). Furthermore, CRTL1 and aggrecan interact in the absence or presence of hyaluronan whereas CRTL1 and versican do not bind directly but form ternary complexes with hyaluronan (Seyfried et al., 2005).

2.3.

The function of ECM in the CNS

Although the ECM has been considered to play predominantly a structural role, it has become clear during the past few years that the CSPGs in the ECM are important in determining the functional responses of cells to their environment during development, cell migration, cell maturation and differentiation, cell survival and tissue homeostasis (Oohira et al., 2000). Many of the functions of CSPGs are due to the presence of CS-GAG chains. CS-GAGs bind various growth-active factors: both growth promoting factors, such as midkine, pleiotrophin and some members of the fibroblast growth factor family (Milev et al., 1998; Hirose et al., 2001; Kawashima et al., 2002; Deepa et al., 2002; Deepa et al., 2004) and growth inhibitory factors such as semaphorins (Kantor et al., 2004; De Wit et al., 2005). This binding may responsible for (1) localization of particular growth-active molecules at defined sites, e.g., in the developing cortex (Emerling and Lander, 1996); (2) regulation of the activity of these molecules, e.g., GAG binding converts semaphorin 5A

from a permissive to an inhibitory molecule (Kantor et al., 2004); (3) stabilization of ligand–receptor binding, promoting signaling; (4) protection of the molecules from degradation; and (5) production of a reservoir of growth-active molecules for future mobilization.

2.4. Perineuronal Nets-specialized organization of the ECM in the CNS In addition to the general loosely organized ECM found throughout the CNS, there are special structures known as PNNs that are highly condensed matrix that surround the cell bodies and proximal dendrites of some classes of neurons (Celio and Blumcke, 1994; Celio et al., 1998; Yamaguchi, 2000; Murakami and Ohtsuka, 2003b). Recent biochemical analyses of rat brain in our laboratory have shown that the composition of the CS-GAG chains associated with the PNNs differ from those in the ECM (Deepa et al., 2006). The components of PNNs are CSPGs including lecticans [brevican (Hagihara et al., 1999), neurocan (Matsui et al., 1998), versican (Bignami et al., 1993; Hagihara et al., 1999), aggrecan (Zaremba et al., 1989)], phosphacan (Wintergerst et al., 1996; Haunso et al., 1999), hyaluronan (Yasuhara et al., 1994), tenascin-R (Hagihara et al., 1999; Weber et al., 1999; Bruckner et al., 2000) and link proteins (Hirakawa et al., 2000; Oohashi et al., 2002; Bekku et al., 2003). Tenascin-C was suggested to be a component of PNNs (Celio and Chiquet-Ehrismann, 1993). Further information on the importance of the various components for normal PNN formation has come from CSPGs and tenascin knockout mice. Recent observations in the tenascin-C knockout mice have shown that the appearance of PNNs was normal, indicating tenascin-C is not a crucial component of PNNs (Irintchev et al., 2004). Mice deficient in neurocan (Zhou et al., 2001) or brevican (Brakebusch et al., 2002) were anatomically and morphologically similar to wild-type mice. However, in tenascin-R-deficient mice, the staining intensity of the PNNs is reduced for brevican, hyaluronan and neurocan and it is

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broken up into globules (Bruckner et al., 2000) suggesting that tenascin-R is an important component of PNNs. After the quadruple knockout of neurocan, brevican, tenascin-R and tenascin-C, PNNs were present but difficult to identify (Rauch et al., 2005). There has been a longstanding debate on the cellular origin of CSPGs in PNNs (Celio et al., 1998). Recent experiments from our laboratory examining PNNs in the rat cerebellum have used in situ hybridization to identify the cell types making the various components and have shown that some CSPGs are produced and expressed by neurons, some by glia and some are expressed by both neurons and glia (Carulli et al., 2006). CSPGs expressed by neurons include aggrecan (Lander et al., 1997; Matthews et al., 2002) and neurocan (Engel et al., 1996). Brevican is expressed by both neurons (Seidenbecher et al., 2002) and astrocytes (Ogawa et al., 2001) while phosphacan and RPTPβ are produced by both glial and neuronal cells (Shintani et al., 1998; Hayashi et al., 2005). Versican is expressed by oligodendrocytes and oligodendrocyte precursor cells (Asher et al., 2002). Recently it has been suggested that cultured cortical neurons are able to construct PNN-like structure without glial cells (Miyata et al., 2005a). Several possible mechanisms for the organization of PNNs have been suggested (Yamaguchi, 2000; Fox and Caterson, 2002; Murakami and Ohtsuka, 2003a). Once the CSPGs are produced, they must be attracted to the neurons and attached to the neuronal cell surface. There have been several proposed mechanisms for this linkage, including a collagenous ligand (Murakami et al., 1999a; Murakami et al., 1999b), core proteins (Koppe et al., 1997b) and cell surface-associated CSPGs such as aggrecan (Lander et al., 1997; Matthews et al., 2002), brevican (Seidenbecher et al., 2002) and phosphacan (Hayashi et al., 2005) or transmembrane CSPGs such as NG2 and neuroglycan-C, phosphacan binding to NCAM (Fox and Caterson, 2002). Recently, another possible mechanism for the formation of condensed ECM in PNNs was suggested. Hyaluronan is the key organizer of the chondrocyte pericellular matrix (Knudson et al., 1999; Knudson and Knudson, 2001). The crucial role of hyaluronan in maintenance of PNNs is supported by the fact that digestion of hyaluronan with the enzyme hyaluronidase results in the complete removal of PNNs (Koppe et al., 1997b). Hyaluronan interacts with cell surfaces in at least two ways (Toole, 2004). Firstly, it can bind to specific cellsurface receptors, such as CD44 and RHAMM (receptor for hyaluronic-acid-mediated motility). However, this does not appear to be the case in the CNS as in the uninjured CNS CD44 is only expressed by astrocytes and RHAMM is entirely intracellular in neurons (Carulli et al., 2006). Secondly, hyaluronan can be attached to the cell is by retention at the cell surface by sustained transmembrane interaction with hyaluronan synthase, the enzyme that produces it. In situ hybridization shows the isoforms hyaluronan synthase 2 and hyaluronan synthase 3 are present only in those neurons in the cerebellum that are surrounded by PNNs (Carulli et al., 2006). Assuming that the molecular interactions in the PNNs are similar to those described above, it is possible to propose a structural organization of the PNNs taking into account the recent increased understanding of link proteins and hyaluronan synthases (Fig. 3).

PNNs are only present around specific types of neurons in the cortex, hippocampus, thalamus, brainstem and spinal cord (Bertolotto et al., 1996; Vitellaro-Zuccarello et al., 2001). For example, immunohistochemical studies of rat brain have shown that the cortex contains high numbers of PNNs in motor and primary sensory areas and fewer in the association and limbic cortices (Bruckner et al., 1994; Hausen et al., 1996; Bruckner et al., 1996). Cortical PNNs are associated with GABAergic interneurons and certain pyramidal neurons (Hausen et al., 1996; Hartig et al., 1999) and many of the PNN-associated interneurons express parvalbumin (Hartig et al., 1992; Morris and Henderson, 2000) and the voltage-gated potassium channel subunit Kv3.1b (Hartig et al., 1999). In addition, the intensity and morphology of the PNNs (as labeled cyctochemically by N-acetylgalactosamine-binding Wisteria floribunda agglutinin (WFA) an established marker for PNNs (Hartig et al., 1992)) varies in different cells, with pyramidal cells having more delicate PNNs than the interneurons (Hausen et al., 1996; Wegner et al., 2003). In some regions, such as the cortex, the PNNs surrounding different types of neurons have different combinations of CSPGs but the functional consequences of this heterogeneity are not understood (Bruckner et al., 1996; Ojima et al., 1998; Matthews et al., 2002). In the deep cerebellar nucleus, the PNNs contain a mixture of all of the CSPG core proteins (Carulli et al., 2006) but in the cortex there is more specificity with a subset of inhibitory interneuronal PNNs contain neurocan (Pizzorusso et al., 2002) and pyramidal neuronal PNNs contain aggrecan (Lander et al., 1997). Furthermore, biochemical analysis of rat CNS shows glycosylation of the aggrecan in PNNs varies in different areas of the CNS (Matthews et al., 2002). The cell-type-specific development of PNNs is regulated by patterns of intrinsic activity in vitro in cell culture (Berghuis et al., 2004), in organotypic slice culture (Bruckner et al., 2004) and in vivo in the motoneurons of the hamster spinal cord (Kalb and Hockfield, 1988; Kalb and Hockfield, 1990), cat lateral geniculate nucleus (Sur et al., 1988) and visual cortex of rat and cat (Lander et al., 1997; Pizzorusso et al., 2002). Immunohistochemical studies show the formation of PNNs begins during late postnatal development, during the periods characterized by synaptic refinement, myelination and development of an adult-like pattern of physiological activity of neurons (Koppe et al., 1997a).

3. Functions of chondroitin sulfate proteoglycans and plasticity in the adult central nervous system The function of PNNs is not fully established but there are several possibilities: (i) synaptic stabilization and limitation of synaptic plasticity (Hockfield et al., 1990; Corvetti and Rossi, 2005), (ii) support of ion homeostasis around highly active types of neurons (Hartig et al., 1999) or (iii) neuroprotection (Bruckner et al., 1999; Hartig et al., 2001b; Morawski et al., 2004). CSPG are important in the development, maintenance and ageing of the normal CNS. CSPGs have many roles during development and readers wishing to read about these functions are referred to recent reviews (Bandtlow and

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Fig. 3 – Hypothesis of construction of perineuronal nets (PNNs). We suggest that hyaluronan provides a scaffold for the perineuronal net (PNN). Hyaluronan is attached to the neuronal cell surface either through retention by hyaluronan synthase, by another hyaluronan receptor that has not been examined in this study such as layilin or possibly by attachment to cell surface proteoglycans such as RPTPβ. The lectican family of chondroitin sulfate proteoglycans (CSPGs) bind hyaluronan through their N-terminal G1 domains. The interaction between CSPGs and hyaluronan is stabilized by link proteins. Link protein contains two hyaluronan-binding link modules and one module of the immunoglobulin type. Lecticans bind to the fibronectin-like domain of tenascin-R (T-R) via their C-terminal domain (except neurocan-N). Each monomer has a cysteine-rich segment at the N-terminal, an EGF-like domain, fibronectin-like domain and a fibrinogen-like domain at the C terminal. T-R exists as dimers (not shown) and trimers that allow T-R to cross-link the CSPG to form PNNs. The lectican aggrecan has an important role in the PNNs structure whereas other lecticans such as neurocan, versican and brevican, although present, are not critical. Phosphacan is also a component of the PNN via its interaction with T-R. Phosphacan is not able to bind hyaluronan.

Zimmermann, 2000; Oohira et al., 2000; Carulli et al., 2005). In the adult CNS there is emerging evidence that CSPGs are involved in the control of plasticity (Rhodes and Fawcett, 2004). There are two main types of plasticity: (i) synaptic plasticity, which is defined as activity-dependent changes in the efficacy of synaptic transmission across existing synapses; and (ii) anatomical plasticity (also known as structural plasticity or remodeling), which is defined as change in the anatomical arrangement of neural connections with the

formation of new synapses (Fawcett et al., 2002). Plasticity plays a key role in the refinement of connections during development but a lower level of plasticity continues in the adult CNS in response to experience, age or injury.

3.1. The role of CSPGs in plasticity during postnatal development-ocular dominance plasticity During early life, the environment influences the shaping of neural circuits, particularly during developmental windows

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called critical periods. A critical period is a stage when appropriate experience is essential for organization of a pathway or set of connections and absence of appropriate experience may lead to formation of incorrect neural connections forming. In many parts of the CNS, there is a sudden end to the critical period, after which connections are stable and manipulation of experience will only produce minor changes. Some critical periods are well defined but critical periods for sensory and motor skills are longer and less well defined (Hensch, 2004). A much studied critical period is that of the developing visual system (Berardi et al., 2000). In the mature primary visual cortex of higher mammals, most neurons respond predominantly to visual inputs from either the left eye or the right eye, ocular dominance. Cells that respond to a given eye are arranged in stripes, the ocular dominance columns, alternating with stripes of neurons that respond to the other eye. If vision is normal for both eyes during development, each eye drives equal numbers of neurons, but if one eye is occluded during development, the majority of visual cortical neurons become dominated by the non-deprived eye. In the cat, the critical period lasts for six to eight weeks after birth and in the monkey it is roughly 16 weeks. It is estimated that in humans the critical period may extend up to five years of age. The many mechanisms underlying ocular dominance plasticity and its termination have been reviewed elsewhere (Berardi et al., 2003). Recently, it has been shown that PNNs have a role in closure of the critical period in the visual cortex of the rat. Dark rearing, which prolongs the critical period closure, also delays CSPG condensation in both cats (Hockfield et al., 1990; Lander et al., 1997) and rats (Pizzorusso et al., 2002). Moreover, digestion of PNNs using the bacterial enzyme chondroitinase ABC (ChABC) “reopens” the critical period. ChABC, an enzyme from the bacteria Proteus vulgaris, catalyzes the removal of CS-GAG chains of CSPGs (Prabhakar et al., 2005). Treatment of the visual cortex of adolescent rats (postnatal day (P)70) with ChABC reactivated ocular dominance plasticity after the critical period (Pizzorusso et al., 2002; Fox and Caterson, 2002). Furthermore, if rats are monocularly deprived at P22 (before the end of the critical period) until adulthood (P120– P300), the bias of ocular dominance towards the nondeprived eye becomes irreversible and visual acuity is diminished producing a situation directly analogous to amblyopic humans. However, digestion of PNNs with ChABC allowed visual experience to drive normalization of neural connections and complete recovery of ocular dominance, visual acuity and dendritic spine density in adult rats as shown by anatomical, electrophysiological and behavioral methods. (Pizzorusso et al., 2006).

telyan et al., 2001; Bukalo et al., 2001). However, the mechanism is currently unknown. One possibility is that the binding of growth factors to CS-GAG, for instance pleiotrophin inhibits LTP in hippocampus (Amet et al., 2001) and binds to the CSGAG chain of neurocan and phosphacan (Milev et al., 1998). The removal of the CS-GAG could result in the release of growth factors that play a part in LTP. It is not known if the effect of CSPGs on LTP is purely due to the CS-GAG chains or if the core proteins also have a role. An analysis of hippocampal slices of mice deficient in neurocan showed normal early phase-LTP, while late phaseLTP was impaired (Zhou et al., 2001). LTP was abolished in mice that were deficient in brevican and also after injection of anti-brevican antibodies (Brakebusch et al., 2002). Although the mechanisms underlying the contribution of brevican to synaptic plasticity is currently not clear, it is possible that the interaction of brevican with the HNK-1 carbohydrate which also localizes to PNNs in the hippocampus is involved (Dityatev and Schachner, 2003). One of the main carriers of the carbohydrate HNK-1 is tenascin-R and these mice also show impaired LTP (Saghatelyan et al., 2001; Bukalo et al., 2001) and also behavioral deficits (Freitag et al., 2003). The difference effects of neurocan and brevican suggests that different CSPGs are involved in distinct stages of LTP through mechanisms that have not yet been identified.

3.3. The role of CSPGs in structural plasticity in the adult CNS–hypothalamo–neurohypophysial system plasticity The hypothalamo-neurohypophysial system is composed of the neurohypophysis (posterior pituitary) and paraventricular and supraoptic nucleus of the hypothalamus. This system reveals dramatic structural plasticity in response to chronic stimulation such as salt loading and lactation which is associated with changes in antidiuretic hormone (ADH) and oxytocin production respectively (Theodosis et al., 2004). In the supraoptic nucleus, the structural plasticity is associated with the retraction of glial cells between magnocellular neurons, which results in the direct apposition of the neuronal membranes and the formation of multiple synapses. Immunohistochemistry shows that phosphacan/RPTPβ is present in PNNs surrounding ADH-containing cell bodies and dendrites in the supraoptic nucleus of the adult rat hypothalamus. Chronic salt loading, which is known to induce structural plasticity, decreased phosphacan/RPTPβ levels. These phosphacan/RPTPβ levels returned to normal three weeks after cessation of the chronic stimulation (Miyata et al., 2004). This suggests that the levels of the CSPG phosphacan are regulated in an activity-dependent manner and may be concerned with the structural plasticity.

3.2. The role of CSPGs in synaptic plasticity in the adult CNS-learning and memory There is evidence for a role of CSPGs in the plasticity that underlies learning and memory, long-term potentiation (LTP) (Malenka and Nicoll, 1999) and long-term depression (LTD) in the CA1 region of the adult hippocampus (Dityatev and Schachner, 2003). Removal of CS-GAG chains reduced both LTP and LTD in murine hippocampal slice cultures (Sagha-

4. Chondroitin sulfate proteoglycans and CNS pathology CSPGs have an important role in various diseases and injuries in the CNS. After CNS injury, CSPGs contribute to the inhibition of axonal regeneration and restrict plasticity. The role of CSPGs in diseases such as epilepsy, stroke and

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Alzheimer's disease is less clear. However, the emerging evidence suggests that changes in CSPGs may affect these disease processes.

4.1. Chondroitin sulfate proteoglycans and traumatic central nervous system injury Traumatic injury of the adult CNS results in glial scar formation, degeneration of denervated and damaged neurons and collateral sprouting of surviving axons. CSPGs have two major effects after CNS injury: (i) inhibition of axonal regeneration (Matsui and Oohira, 2004) and (ii) restricting plasticity (Rhodes and Fawcett, 2004).

4.1.1. Chondroitin sulfate proteoglycans, central nervous system injury and inhibition of axonal regeneration CSPGs are the main axon growth inhibitory molecules in the glial scar and play a crucial part in the failure of axon regeneration after injury (Silver and Miller, 2004). Expression of many CSPGs, including neurocan, versican, brevican and NG2, increase after injury to the rat brain (Moon et al., 2002) and spinal cord (Tang et al., 2003; Jones et al., 2003) although there is a decrease in aggrecan core protein after spinal cord injury (Lemons et al., 2001) and phosphacan levels initially decline then increase (Morgenstern et al., 2002). Most of CSPGs are inhibitory to axonal outgrowth (Snow et al., 1996). Removal of the CS-GAG chains with ChABC removes most of the inhibitory activity of CSPGs and glial cells in vitro (SmithThomas et al., 1995; McKeon et al., 1995). In vivo, treatment with ChABC enhances the regeneration of the axons of dopaminergic neurons (Moon et al., 2001) and promotes axonal regeneration and functional recovery after spinal cord injury (Bradbury et al., 2002; Yick et al., 2003; Caggiano et al., 2005). ChABC has also been demonstrated to be an effective treatment to promote axonal regeneration after spinal cord injury in combination with lithium chloride (Yick et al., 2004), Schwann cell-seeded guidance channels (Chau et al., 2004) and Schwann cell bridges and olfactory-ensheathing glia grafts (Fouad et al., 2005; Houle et al., 2006). Sulfation is necessary for CS-GAGs to be inhibitory as preventing GAG sulfation makes inhibitory glia more permissive (Smith-Thomas et al., 1995). However, the subtypes of CSGAGs vary in their ability to block axon regeneration. The 6sulfated CS-GAG (CS-C) is particularly inhibitory (Snow et al., 1990) whereas 2,6-sulfated CS-GAG (CS-D) and 4,6 sulfated CSGAG (CS-E) promotes elongation of embryonic axons in vitro (Clement et al., 1998; Clement et al., 1999). In addition to the general upregulation of CSPGs, there is also a change in the sulfation pattern of the GAG chains after injury. The most prominent sulfated GAG disaccharide within normal CNS is 4sulfated (CS-A). After injury, there is a change in the GAG composition although there is some disagreement as to its nature. One study analyzed the mRNA levels of the CS-GAG synthesizing enzymes and measured the CS-GAG disaccharide composition by chromatography and immunocytochemistry in rat brain to show an increase in the CS-GAG chains monosulfated in the 6 position of the GalNAc residue (CS-C) and its respective synthetic enzyme, chondroitin 6-sulfotransferase 1 (Properzi et al., 2005). Another report used fluoro-

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phore-assisted carbohydrate electrophoresis of injured rat brain to show that most prominent sulfated GAG disaccharide in the scar of the injured cortex was 4,6-sulfated (CS-E) (Gilbert et al., 2005).

4.1.2.

CSPGs, CNS injury and plasticity

Recovery from CNS damage is usually poor because of the limited capacity of the adult CNS for reorganization after injury (Chen et al., 2002). CSPGs have a role in restricting plasticity after injury. In the hippocampus, after unilateral entorhinal cortex lesion, there is reorganization of the fascia dentata that is accompanied by changes in CSPGs, which are rapidly upregulated after injury. The CSPGs may contribute to the layer specific sprouting response of the surviving axons (Deller et al., 2001) and stabilization of newly formed synapses (Thon et al., 2000). In the rat cerebellum, degradation of CS-GAG chains by treatment with ChABC promotes structural plasticity of Purkinje axons (Corvetti and Rossi, 2005). Also after injury, ChABC injections into the partially denervated superior colliculus increase sprouting of the remaining retinal ganglion cell axons into the collicular scotoma (Tropea et al., 2003). Following spinal cord injury, rats that have been treated with ChABC show regrowth of axons into the denervated territory and recovery of motor and bladder function (Bradbury et al., 2002; Caggiano et al., 2005). It is likely that some of the recovery of function was due to an increase in the limited plasticity normally seen after spinal cord injury (Edgerton et al., 2004) rather than axon regeneration as the time course of the recovery was so rapid (within 14–21 days). Digestion of CSPGs also enhances plasticity of intact systems within the brainstem and spinal cord after spinal cord injury (Barritt et al., 2006). Furthermore, a functional change, shown by electrophysiology, directly linked to anatomical evidence of sprouting by spinal cord afferents, after ChABC treatment has recently been shown after rat spinal cord injury (Massey et al., 2006). After peripheral nerve injury, plasticity occurs at both cortical and subcortical levels (Wall et al., 2002). The motoneurons in the ventral horn of the spinal cord are surrounded by PNNs (Bodega et al., 1985; Bertolotto et al., 1996; Takahashi-Iwanaga et al., 1998). Their development is dependent on normal activity during early life, but they show greater stability in adults where nerve injury has no effect on the pattern of aggrecan in the PNNs (Kalb and Hockfield, 1988; Kalb and Hockfield, 1990). However, tenascin-R, another component of the PNNs is less stable and is partly removed after peripheral nerve axotomy in the facial nerve injury rat model (Angelov et al., 1998). Recovery of function after facial nerve injury and repair was better in tenascin-R null mice, that have abnormal PNNs (Bruckner et al., 2000), compared with wild-type littermates (Guntinas-Lichius et al., 2005). It is an intriguing possibility that removal of PNNs may allow plasticity after peripheral nerve injury. Preliminary data suggest that ChABC encourages plasticity of intact primary afferents, which may lead to a restoration of sensory function after deafferentation (Cafferty et al., 2004). Recent work in our laboratory also suggests that ChABC improves functional recovery after peripheral nerve injury (Galtrey et al., in press).

10 4.2.

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The role of CSPG in the pathogenesis of CNS disease

Recent investigations have shown that there are alterations in CSPGs in several diseases including epilepsy, stroke and Alzheimer's disease that may be significant in disease pathology.

4.2.1.

Epilepsy

The abnormal electrical activity associated with epilepsy generates plastic changes that play a part in the pathogenesis of the disease (Morimoto et al., 2004). CSPGs are partly removed from the hippocampus in epilepsy and these changes may be important in allowing the sprouting to occur. After seizures, there is a decrease in phosphacan and phosphacan-positive PNNs (Okamoto et al., 2003) and increase the presence of cleaved brevican in the temporal lobe and hippocampus (Yuan et al., 2002). Seizures have also been shown to increase the deposition of full-length neurocan in association with axonal sprouting in the dentate gyrus. (Okamoto et al., 2003). Full-length neurocan is dominant in the neonatal brain, whereas neurocan is almost exclusively present as the proteolytically cleaved N-terminal half fragment (neurocan-N) and a C-terminal half fragment (neurocanC) in the adult rat brain (Asher et al., 2000). Thus, there are several change in CSPGs in epilepsy suggesting that they may play a part in the control of axonal extension and sprouting (Heck et al., 2004).

4.2.2.

Stroke

After stroke, plasticity occurs in peri-infarct and remote regions resulting in the reorganization of cortical maps which is associated with some return of function (Carmichael, 2003) and this is accompanied by changes in CSPGs that may enable plasticity. After stroke, immunohistochemistry of rat brain showed there is a reduction in the PNNs in the peri-infarct region between days 7 and 14 after both a photochemical lesion (Bidmon et al., 1997) and a middle cerebral artery occlusion (Hobohm et al., 2005) with reductions in aggrecan, versican and phosphacan (Carmichael et al., 2005). This downregulation of PNNs also occurred in remote thalamic nuclei (Hobohm et al., 2005). In addition, there is accumulation of the full-length neurocan after stroke (Carmichael et al., 2005; Deguchi et al., 2005).

4.2.3.

Alzheimer's disease

The roles of CSPGs in Alzheimer's disease appear to be multiple. Both neuroprotective and neuropathological roles have been proposed for the PNNs. Some studies report a reduction in the number of PNNs in human Alzheimer's diseased brains (Kobayashi et al., 1989; Baig et al., 2005) whereas others report no change (Bruckner et al., 1999). PNNs may provide protection against excitotoxicity (Okamoto et al., 1994), oxidative stress (Morawski et al., 2004) and the formation of neurofibrillary tangles (Bruckner et al., 1999; Hartig et al., 2001a). The cortical distribution of neurofibrillary tangles in Alzheimer's disease brains matches the pattern of neurons that retain their capacity for plastic remodeling (Arendt et al., 1998). There is also a lack of consensus as to the susceptibility in Alzheimer's disease of the parvalbumin-positive neurons

that constitute a high proportion of those surrounded by PNNs (Satoh et al., 1991; Solodkin et al., 1996; Brady and Mufson, 1997;Sampson et al., 1997). Conversely, colocalization of some proteoglycans with amyloid β-peptide (Aβ) and neurofibrillary tangles may reflect a pathogenic role of the PNNs in Alzheimer's disease (DeWitt et al., 1993; Fillit and Leveugle, 1995; Goedert et al., 1996; Bruckner et al., 1999; Diaz-Nido et al., 2002). CSPGs colocalize with both amyloid plaques and neurofibrillary tangles suggesting either that they could be instrumental in the formation of these deposits or that they are a reaction to them (DeWitt et al., 1993; McLaurin and Fraser, 2000). In vitro studies demonstrate that CSPGs and GAGs promote Aβ fibril formation and binding of GAGs to Aβ has been shown to inhibit the proteolysis of Aβ fibrils (GuptaBansal et al., 1995). Aβ is a very strong stimulant to astrocytic CSPGs production and these CSPGs are particularly inhibitory to neuronal process growth and may facilitate the decreased axon density and synaptic loss in human Alzheimer's diseased brain (DeWitt et al., 1994; DeWitt and Silver, 1996).

4.3.

Mechanisms of CSPG regulation

Some common ideas are beginning to emerge from the current information on the role of CSPG in CNS disease. PNNs are probably important for synaptic stabilization and preventing plasticity (Hockfield et al., 1990). PNNs do not form until late in postnatal development after synaptic refinement has taken place and neurons have acquired their mature phenotype and PNNs remain stable throughout adult life and matrix turnover appears to be slow (Bruckner et al., 1998). However, there appears to be a mechanism for the removal of PNNs after a CNS insult, such as epilepsy or stroke that could allow some reactivation of plasticity, so promoting recovery. Extracellular proteolysis provides an attractive mechanism by which neuronal processes could remodel their synaptic connections (Shiosaka and Yoshida, 2000). Possible candidates are tissue plasminogen activator, matrix metalloproteases and ADAMs (a disintegrin and metalloproteinase). Tissue plasminogen activator has been shown to promote plasticity in the visual cortex (Muller and Griesinger, 1998; Berardi et al., 2004; Oray et al., 2004) and in the hypothalamo-neurohypophysial system (Miyata et al., 2005b). Matrix metalloproteinases are expressed at significant levels in regions of neuronal plasticity in the adult CNS, such as the cerebellum (Vaillant et al., 1999; Hayashita-Kinoh et al., 2001), and may also be concerned with the structural plasticity in the hypothalamo-neurohypophysial system (Miyata et al., 2005b). Matrix metalloproteinases also are rapidly upregulated after nearly all types of CNS insult, including spinal cord injury (Xu et al., 2001), Alzheimer's disease (Yoshiyama et al., 2000) and stroke (Sole et al., 2004; Nagel et al., 2005). Furthermore, matrix metalloproteinase 5-deficient mice did not develop neuropathic pain or associated sprouting after sciatic nerve injury (Komori et al., 2004). After epileptic seizures in rats, in situ hybridization showed there is a dramatic increase in ADAMs 1 and 4 that correlates and colocalizes with the presence of cleaved brevican (Yuan et al., 2002). Therefore, it appears that PNNs are cleaved by specific matrixdegrading proteases after the insult. This removal of the PNNs

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Fig. 4 – Biosynthesis of chondroitin sulfate proteoglycans and possible targets for therapeutic intervention. The core protein DNA is transcribed in the nucleus. Synthesis of the core protein starts in cytoplasmic ribosomes, which attach to the rough endoplasmic reticulum. The protein chain is then transferred to the Golgi apparatus, where glycosylation occurs. Selected groups are then sulfated by sulfotransferase. Once sulfation is completed, the molecules are packed into secretary vesicles and transported to the cell surface where they are released into the extracellular matrix. The synthesis of CSPGs is under hormonal control. For example, interleukins 1 and 6 inhibit their synthesis whereas transforming growth factor β (TGFβ) stimulate synthesis. Depletion of CSPGs has been shown to promote axonal regeneration and plasticity. Various strategies have been used to decrease CSPGs in both the normal and injured central nervous system (CNS): (1) Chondroitinase ABC is an enzyme extracted from the bacterium P. vulgaris that removes the GAG side chains. It is the CS-GAG chains of the CSPGs that are inhibitory to axon outgrowth and restrict plasticity therefore removal of the GAG chains from both endogenous CSPG in the normal CNS and upregulated CSPGs in the glial scar after injury has therapeutic potential to promote both regeneration and plasticity. (2) DNA enzyme to degrade mRNA of xylosyltransferase results in the absence of the first enzyme required for GAG synthesis. This results in a reduction of presence of the inhibitory GAG chains. Possible future targets would include the other enzymes in this pathway. This is a useful technique to reduce the inhibitory GAG chains on the CSPGs rapidly upregulated after CNS injury but may be less useful to promote plasticity as endogenous CSPGs have a slow turnover rate. (3) Inhibiting the Rho/ROCK pathway with either a PKC inhibitor, Rho-GTPase inhibitor or ROCK inhibitor blocks one of the intracellular pathways that may mediate some of the inhibitory effects of CSPGS to prevent axon regeneration. This may be a useful technique to block the inhibitory effects of CSPGs in both the normal and injured CNS. (4) Decorin suppresses the expression of CSPGs core proteins after injury by inhibiting the activity of TGFβ. TGFβ induces the upregulation of CSPG synthesis by increasing transcription. This may be a useful technique to prevent the upregulation of CSPGs after CNS injury.

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may be the event that allows synaptic reorganization to occur. The destruction of PNNs may occur in parallel with or precede the upregulation of more juvenile ECM components, such as full-length neurocan. This increase in the expression neurocan may serve to define axonal extension and control and limit aberrant axonal sprouting (Rauch, 2004).

5. Therapeutic potential of manipulating CSPGs in the CNS CSPGs have an important role in many aspects of CNS function in the development, maintenance and aging of the normal CNS and in the pathogenesis of injuries and disease. Removing CSPGs promotes plasticity providing potential treatments for CNS injuries, strokes and neurodegenerative diseases. There are an increasing number of potential treatment options to manipulate CSPGs in the CNS (Fig. 4). Firstly, as discussed above, ChABC enhances axonal regeneration after nigrostriatal tract lesioning (Moon et al., 2001) and spinal cord injury (Bradbury et al., 2002; Yick et al., 2003; Caggiano et al., 2005) and restored plasticity to the visual cortex (Pizzorusso et al., 2002; Pizzorusso et al., 2006). The mechanism by which ChABC promotes plasticity is not proven but recent studies have shown that ChABC induces axonal sprouting of Purkinje cells both in slices cultures (Tanaka et al., 2003) and in vivo (Corvetti and Rossi, 2005) and allows plasticity to occur. The increased axonal sprouting may occur as a result of the decreased the amount of pleiotrophin after treatment with ChABC (Shimazaki et al., 2005). Another method developed to reduce expression of CSGAG chains is a DNA enzyme designed to degrade the mRNA of the enzyme, xylosyltransferase-1 that initiates GAG synthesis on core proteins. When this enzyme was infused around an injury site there was reduced expression of CS-GAG chains in the injured rat spinal cord and improved axonal regeneration (Grimpe and Silver, 2004). It may also be possible in the future to target other enzymes in the CS-GAG synthesis pathway such as CSST enzymes (Laabs et al., 2005). The Rho/ROCK pathway may mediate some of the inhibitory effects of CSPGs on axon growth. Suppression of this pathway promoted axonal regeneration either by inhibition of protein kinase C (Sivasankaran et al., 2004), Rho GTPase (Monnier et al., 2003) or ROCK (Fournier et al., 2003). It has also been suggested recently that CSPGs signal via the epidermal growth factor receptor (Koprivica et al., 2005). Pharmacologically blocking other downstream signaling from CSPGs may also enhance CNS regeneration. Transforming growth factor β (TGFβ) stimulates the synthesis of CSPG core proteins (Asher et al., 2000). Antibodies against TGFβ result in a reduction of glial scar formation after rat brain injury (Moon and Fawcett, 2001). Decorin inhibits the activity of TGFβ. Administration of decorin to injured sites in the adult rat brain (Logan et al., 1999) and spinal cord suppresses expression of several CSPG, such as neurocan, brevican, phosphacan and NG2, and promoted axon growth across adult rat spinal cord injuries (Davies et al., 2004). All these treatments suggest that depletion of CSPGs, CSGAG or their intracellular signals has therapeutic potential.

The type of treatment chosen will depend on the clinical situation. For example, inhibition of the synthesis of CSPGs would be useful to prevent the upregulation of CSPG after CNS injury but it may be necessary to remove the endogenous ECM to reactivate plasticity because CSPGs are stable in the ECM and turn over slowly. It takes eight weeks to reform PNNs after removal of CS-GAG chains (Bruckner et al., 1998). In this situation, it would be more appropriate to digest the CSPGs actively with an enzyme such as ChABC. Clearly, the removal of the CSPGs and PNNs is beneficial if it allows axon regeneration and plasticity but it is possible that the PNNs also have a neuroprotective function. Neurons ensheathed by PNNs are less frequently affected by lipofuscin accumulation than neurons without PNNs both in normal-aged brain and Alzheimer's disease (Morawski et al., 2004). Also the disappearance of the PNNs has been suggested to represent one of the earliest morphological signs of a disturbed brain integrity in Creutzfeldt–Jakob disease (Belichenko et al., 1999; Moleres and Velayos, 2005). Brains derived from human AIDS patients displayed abnormalities in the composition of their PNNs that varied according to the severity of the illness. (Belichenko et al., 1997). Destruction of the ECM components may also precede the death of neurons in macaques after experimental lentiviral infection (MedinaFlores et al., 2004). It is possible to speculate that short-term degradation PNNs allows plasticity, but if these PNNs are absent for long periods the neurons may be left vulnerable to damage although there has been no evidence of this to date. These are important considerations now that ChABC is being widely expected to be a useful therapy after CNS damage.

Acknowledgments The authors would like to thank Tracy Laabs and Daniela Carulli for careful reading of the manuscript and Richard Asher for useful discussions. Clare Galtrey received a fellowship from Merck Sharp and Dohme.

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