Neuroscience 253 (2013) 194–213 NEUROSCIENCE FOREFRONT REVIEW TARGETING THE NEURAL EXTRACELLULAR MATRIX IN NEUROLOGICAL DISORDERS S. SOLEMAN, a M. A. FILIPPOV, b,c A. DITYATEV b,c,d* AND J. W. FAWCETT a in regeneration, stroke, and amblyopia. In addition to CSPGs, this review also points to the functions and potential therapeutic value of these and several other key ECM molecules in epileptogenesis and dementia. Ó 2013 IBRO. Published by Elsevier Ltd. All rights reserved. a Cambridge Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom b Molecular Neuroplasticity Group, German Center for Neurodegenerative Diseases (DZNE), 39120 Magdeburg, Germany Key words: extracellular matrix, plasticity, proteoglycans, perineuronal nets, spinal cord injury, epilepsy. c Laboratory for Brain Extracellular Matrix Research, University of Nizhny Novgorod, 603950 Nizhny Novgorod, Russia d Otto-von-Guericke University, 39120 Magdeburg, Germany Contents The role of the extracellular matrix 194 Extracellular components and function 195 The role and importance of perineuronal nets in system plasticity 196 Role of semaphorins and Otx2 in developmental plasticity 197 Targeting the extracellular matrix in neurological disorders 198 Traumatic central nervous system injury 199 Targeting the ECM and glial scar after spinal cord injury 199 Targeting the ECM and glial scar after stroke 201 Amblyopia and disorders of the visual system 201 Extracellular matrix and epilepsy 202 Extracellular matrix and Alzheimer’s disease 204 Acknowledgments 207 References 207 Abstract—The extracellular matrix (ECM) is known to regulate important processes in neuronal cell development, activity and growth. It is associated with the structural stabilization of neuronal processes and synaptic contacts during the maturation of the central nervous system. The remodeling of the ECM during both development and after central nervous system injury has been shown to affect neuronal guidance, synaptic plasticity and their regenerative responses. Particular interest has focused on the inhibitory role of chondroitin sulfate proteoglycans (CSPGs) and their formation into dense lattice-like structures, termed perineuronal nets (PNNs), which enwrap sub-populations of neurons and restrict plasticity. Recent studies in mammalian systems have implicated CSPGs and PNNs in regulating and restricting structural plasticity. The enzymatic degradation of CSPGs or destabilization of PNNs has been shown to enhance neuronal activity and plasticity after central nervous system injury. This review focuses on the role of the ECM, CSPGs and PNNs; and how developmental and pharmacological manipulation of these structures have enhanced neuronal plasticity and aided functional recovery THE ROLE OF THE EXTRACELLULAR MATRIX The extracellular matrix (ECM) provides a microenvironment that regulates neural cell development and activity. It occupies the space between both neurons and glial cells, where these cells secrete diverse molecules that contribute to the composition of the ECM. During CNS development the ECM undergoes significant changes and acts to support neurogenesis, gliogenesis, synaptogensis, cell migration, axonal outgrowth and guidance (Bandtlow and Zimmermann, 2000; Faissner et al., 2010), while in adulthood it affects cell survival, plasticity, damage responses and regeneration (Meredith et al., 1993; Grimpe and Silver, 2002; Dityatev et al., 2010; Kwok et al., 2011). There are substantial changes in both the quantity and the composition of the ECM during the course of development. During early embryonic *Correspondence to: A. Dityatev, Molecular Neuroplasticity Group, German Center for Neurodegenerative Diseases (DZNE), 39120 Magdeburg, Germany. Tel: +49-391-67-24526; fax: +49-3916724530. E-mail address: alexander.dityatev@dzne.de (A. Dityatev). Abbreviations: AD, Alzheimer’s disease; ADDLs, amyloid-derived diffusible ligands; BDNF, brain-derived neurotrophic factor; ChABC, chondroitinase ABC; CSPGs, chondroitin sulfate proteoglycans; ECM, extracellular matrix; GAG, glycosaminoglycan; HSPGs, heparan sulfate proteoglycans; LGI1, leucine-rich, glioma-inactivated 1; LRP1, lipoprotein receptor-related protein 1; LTD, long-term depression; LTP, long-term potentiation; mEPSCs, miniature excitatory postsynaptic currents; MMP, matrix metalloproteinase; OPCs, oligodendrocyte precursor cells; Otx2, orthodenticle homeobox protein 2; PNNs, perineuronal nets; PV, parvalbumin; SCI, spinal cord injury; SRPX2, Sushi-repeat Protein, X-linked 2; uPA, urokinase-type plasminogen activator. 0306-4522/13 $36.00 Ó 2013 IBRO. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neuroscience.2013.08.050 194 S. Soleman et al. / Neuroscience 253 (2013) 194–213 development, the quantity of ECM relative to the cell mass is very high and this gradually declines toward the time of birth. During the same period the composition of matrix proteins and the sulfation patterns of the proteoglycans have been found to also change (Miyata et al., 2012). The final change in the composition of the adult ECM coincides with the end of the critical period (Galtrey and Fawcett, 2007; Carulli et al., 2010), a time of enhanced structural and functional synaptic plasticity. Here, the adult ECM restricts major reorganization of processes and axonal outgrowth, through the differential expression of molecules into adulthood, and the appearance of remarkable cartilage-like structures called perineuronal nets (PNNs) (Bruckner et al., 1993; Dityatev et al., 2007; Carulli et al., 2010). Nevertheless, the adult central nervous system (CNS) still retains a capacity to promote structural plasticity and how this plasticity can be further enhanced by manipulating the ECM will be discussed in this review. Here we focus on a particular aspect, the roles of perisynaptic/synaptic ECM, glial scars and b-amyloid aggregates in the adult diseased CNS, and selectively refer to studies on the ECM of the blood–brain barrier and neurogenic niche, or ECM functions during normal development. EXTRACELLULAR COMPONENTS AND FUNCTION One of the most abundant glycanated protein types found in the nervous system and which form a major ECM component are chondroitin sulfate proteoglycans (CSPGs) (Carulli et al., 2005). They are characterized by a core protein and a number of covalently attached sulfated glycosaminoglycan (GAG) carbohydrate sidechains. These GAG chains are linked to serine residues in core proteins via a three sugar xylose linker, synthesized through the enzyme xylosyltransferase (Gotting et al., 2000). The GAG chains are composed of sulfated polysaccharides consisting of repeating disaccharides. The variations in GAG chain number and degree and position of sulfation determine their functions (Hardingham and Fosang, 1992; Kwok et al., 2008). There are four major groups of CSPGs, and the member that forms the major part of the brain ECM are lecticans (versican, aggrecan, neurocan, brevican) (Bandtlow and Zimmermann, 2000; Matsui and Oohira, 2004; Galtrey and Fawcett, 2007). Other members of the family also include the cell surface-associated neuron-glia 2 (NG2) and phosphacan, and the small CSPG decorin. CSPGs, heparan sulfate proteoglycans (HSPGs) and other matrix molecules play various roles during early development where they pattern cell migration, regulate axonal path finding and axonal guidance. A recurring theme is that proteoglycans localize active molecules to particular places through specific binding to particular sulfation motifs on their glycan chains (Filla et al., 1998; Pye et al., 1998; Deepa et al., 2006). The final stage of neuronal development is a period of enhanced plasticity known as the critical period, during which patterns of 195 connections and synaptic properties mature (Berardi et al., 2003; Hensch, 2005). Following the closure of this period, the level of many forms of plasticity also declines (Carulli et al., 2005; Hensch, 2005; De Vivo et al., 2013). The maturation and connectivity of GABAergic interneurons plays a key part in the closure of critical periods (Hensch et al., 1998; Southwell et al., 2010; Beurdeley et al., 2012). The surprising development in recent years has been the realization that the formation of cartilage-like, CSPG-rich PNNs around these inhibitory interneurons is a key event in the restriction of developmental plasticity and modulation of synaptic properties, and that enzymatic digestion of chondroitin sulfates or transgenic deletion of link protein Crtl1 restores developmental plasticity to the adult CNS (Carulli et al., 2010; Kwok et al., 2011). In contrast, enzymatic digestion of chondroitin sulfates and genetic ablation of brevican or neurocan expression impair synaptic plasticity measured as long-term potentiation (LTP) or depression (LTD) (Zhou et al., 2001; Bukalo et al., 2001; Brakebusch et al., 2002). Thus, during postnatal development CSPGs play an important role in modulating synaptic properties, spine motility and in modulating the levels of structural and functional plasticity (Hunanyan et al., 2010; Kurihara and Yamashita, 2012; Orlando et al., 2012; De Vivo et al., 2013). They progressively accumulate around somatic and dendritic synapses of certain neurons and contribute to the formation of PNNs (Bruckner et al., 2000; Yamaguchi, 2000; Matthews et al., 2002). The composition of PNNs also includes other ECM molecules which contribute to their formation, which include hyaluronan, link proteins and tenascin-R (Carulli et al., 2006) (Fig. 1). Hyaluronan acts as a backbone in PNNs to non-covalently recruit proteoglycans and glycoproteins (Spicer et al., 2003; Frischknecht and Seidenbecher, 2008); while link proteins stabilize the anchorage of lecticans to hyaluronan; and finally the glycoprotein tenascin-R may act to assemble dimers and trimers as well as cross link lecticans (Kwok et al., 2011). The appearance of these PNNs coincides with the end of experience-dependent plasticity during late postnatal development (Pizzorusso et al., 2002). In addition, after CNS injury CSPGs are one of the main neurite growth-inhibitory molecules present in the glial scar and play a crucial part in the failure of axon regeneration. CSPGs have been shown to act as barrier molecules around the glial scar affecting axon growth, particularly through the inhibitory influence of their GAG chains. This was first demonstrated from in vitro studies where dorsal root ganglia (DRG) and cerebellar granule neurons avoided regions rich in CSPGs and preferentially grew on laminin-coated regions (Snow et al., 1990b; Dou and Levine, 1994). Evidence that GAG chains form a major inhibitory component of CSPGs has come mainly from the utilization of the bacterial enzyme chondroitinase ABC (ChABC). ChABC digests CS-GAG chains from the CSPG core protein (Yamagata et al., 1968) and a number of studies have demonstrated ChABC significantly increases growth 196 S. Soleman et al. / Neuroscience 253 (2013) 194–213 Fig. 1. The restriction of structural plasticity by perineuronal nets. PNNs form a physical structure enwrapping the cell soma and proximal processes, particularly around parvalbumin-expressing GABAergic neurons, creating a barrier against the formation of new synaptic contacts (a). Inhibitory components of PNNs, including CSPGs and Sema 3A, act to reduce the neuronal plastic potential, restrict receptor mobility and trap neurotrophic molecules (b). The disruption of PNNs can reactivate plasticity. Destabilization of PNNs with ChABC treatment leads to the degradation of CSPGs and the modification of neuronal connections, such as an increase in glutamate receptor mobility to aid new synaptic connections. Additionally, endogenous neurotrophic factors are potentially liberated and rendered accessible to growing axons (c). permissiveness in an inhibitory environment both in vitro and in vivo. These studies are discussed in more detail below. Collectively, PNNs and CSPGs have received attention as potential targets in the field of neural repair following CNS disorders. Below we focus on their importance and role in structural plasticity and how their disruption aids remodelling and functional recovery. THE ROLE AND IMPORTANCE OF PERINEURONAL NETS IN SYSTEM PLASTICITY The PNNs were originally described by Camillo Golgi as a structure enwrapping the cell soma and extending along the dendrites of particular populations of neurons (Celio et al., 1998). The PNNs may serve several functions, though there is clear evidence from studies that they are centrally involved in neuronal protection and control of plasticity. Typically, in the brain PNNs do not occur in neuromodulatory transmitter systems (Hobohm et al., 1998), but have been found to mainly localize around parvalbumin (PV)-expressing GABAergic interneurons in the CNS, many of which express the fast reactivating voltage-dependent potassium channel subtype Kv3.1b (Bruckner et al., 1993; Hartig et al., 1994). Electrophysiological studies confirmed that PNNs are ensheathing highly active fast-spiking interneurons in vivo and in vitro (Morris and Henderson, 2000; Dityatev et al., 2007). Additionally, PNNs have been found around a majority of neurons in the spinal cord, where they primarily localize around motor neurons in the ventral cord (Matthews et al., 2002; Galtrey et al., 2007). The intimate relationship between PNNs and these sub-populations of neurons has been hypothesized to have a neuroprotective function, with the polyanionic nature of PNNs protecting fast-spiking neurons from excess potassium extruded by the cell during activity (Bruckner et al., 1993). Additionally, it may act to remove neurotransmitters during neuronal firing such as excess glutamate (Morris and Henderson, 2000), which would otherwise prove neurotoxic (Choi and Rothman, 1990). Thus, it proposes PNNs as a suitable regulator of the microenvironment by controlling the diffusion of cations and other molecules to support the high activity of these neurons. Similar functions might be played by the hyaluronic-acid based perisynaptic ECM. PNNs are dense matrix structures composed of inhibitory CSPGs, thus it is proposed that they may S. Soleman et al. / Neuroscience 253 (2013) 194–213 create a barrier against the formation of new synaptic contacts and reduce the plastic potential of neurons. The formation of PNNs coincides with the final step of maturation of the nervous system, the closure of the critical period for plasticity during which the final refinement of developmentally-formed connections occurs (Pizzorusso et al., 2002; Berardi et al., 2004; Deepa et al., 2006). The formation of these PNNs is also modulated by electrical activity and interference with motoneuron activity can block PNN formation around these cells (Kalb and Hockfield, 1994). Recently, it has been shown that the ECM accumulating around mature neurons limited the mobility of glutamate receptors, as well as other molecules having an ectodomain, to move in and out of synapses, and suggested that this mechanism affects short-term synaptic plasticity (Frischknecht et al., 2009). Additionally, a study has shown that the formation of synapses promoted by astrocytes is paralleled by the emergence of PNNs (Pyka et al., 2011). Modification of ECM by ChABC significantly enhanced the number of synaptic puncta, but reduced the amplitude and charge of miniature excitatory postsynaptic currents, and sensitivity to exogenous glutamate. These findings indicate that CS removal can foster the potential for the formation of new synapses, and that perisynaptic CSPGs may contribute to regulation of the density/ activity of glutamate receptors in subsynaptic sites (Pyka et al., 2011). In the visual cortex and other cortical regions, the accumulation of CSPGs into PNNs is completed after the end of the critical period (Koppe et al., 1997a; Pizzorusso et al., 2002). Studies have shown that the critical period for plasticity can be prolonged by dark rearing which prevents the formation of PNNs (Berardi et al., 2003) and that PNN levels are decreased in the peri-infarct region after ischemic stroke to encourage localized structural plasticity (Carmichael et al., 2005). The disruption of PNN components through deletion of the link protein (Carulli et al., 2010), enzymatic digestion of hyaluronan (Koppe et al., 1997b) or CS-GAG chains (Massey et al., 2006) results in destabilization of this structure and enhanced developmental plasticity. It is known from biochemical studies that PNNs can also harbor both growth promoting or repulsive ligands via binding to their chondroitin sulfate GAG chains, which may suggest how it may limit plasticity or enhance it once destabilized. It has been proposed that during early stages of development, components of immature PNNs attract and trap neurotrophic molecules, for example basic fibroblast growth factor (Celio and Blumcke, 1994). Thus, disruption to PNNs could potentially liberate and increase the bioavailability of endogenous neurotrophic factors or other protective mediators rendering them accessible to axons to stimulate neuronal growth. Repulsive cues have also been known to interact with components of the PNNs and the roles of some of these molecules and their contribution to the restriction of synaptic plasticity is described below. In addition, many neurons express the protein tyrosine phosphatase receptor (PTPr) and 197 leukocyte common antigen-related (LAR) receptors, which have now been identified as mediators that signal CSPG inhibition (Shen et al., 2009; Fry et al., 2010; Fisher et al., 2011). Specifically, these CSPG-receptor interactions have been shown to mediate axonal growth inhibition in neurons partially through inactivating Akt and activating RhoA signals (Fisher et al., 2011). ROLE OF SEMAPHORINS AND OTX2 IN DEVELOPMENTAL PLASTICITY A repulsive guidance cue associated with PNNs in the adult CNS are secreted semaphorin 3s (De Wit et al., 2005). Semaphorins include both attractants and repellents, where they are involved in cytoskeletal remodelling during axonal growth, growth cone guidance during early development (Pasterkamp and Giger, 2009) They also have an important effect on synaptic stabilization and plasticity (Pasterkamp and Kolodkin, 2003; Bouzioukh et al., 2006), thus the association of semaphorins with PNNs would have important implications for neuronal plasticity. It has been demonstrated that Sema3A is associated with the cell surface of cultured cells and that they are connected to the ECM through the binding of CSPGs (De Wit et al., 2005). It was also indicated that HSPGs can potentiate Sema3A-mediated growth cone collapse, suggesting that together proteoglycans in the ECM play an important role in the localization and repulsive guidance activity of semaphorins. Recent studies have shown that Sema3A is localized to PNN structures with specific interactions to the CS-E moiety which are enriched within PNNs (Deepa et al., 2006; Vo et al., 2013). The presence of Sema3 localized to PNNs might certainly be expected to have an effect on synapse dynamics and formation of new connections around GABAergic interneurons. The semaphorin receptors neuropilins and plexins are widely expressed in the adult CNS, including around PNNs (Vo et al., 2013). Moreover, blocking neuropilin-1 function with virallyexpressed receptor bodies can restore ocular dominance plasticity in the adult CNS (Boggio et al., 2012). Additionally, after CNS injury Sema3 has been shown to be expressed by glial scar-associated meningeal cells in neural scar tissue which would add to the repulsive effects of Sema3 on axonal growth after injury (Pasterkamp et al., 1998). Semaphorins are also known to influence synaptic transmission (reviewed by (Dityatev et al., 2008)). Application of exogenous Sema3A is shown to decrease the efficacy of synaptic transmission in hippocampal slices (Bouzioukh et al., 2006). In contrast, Sema3F modulates fast excitatory synaptic transmission by increasing the frequency and amplitude of AMPA receptor-mediated miniature excitatory postsynaptic currents (mEPSCs) in hippocampal slices (Sahay et al., 2005), suggesting Sema3A and Sema3F possess opposing roles in transmission. Interestingly, different classes of semaphorins have been shown to interact with proteoglycans to initiate axonal growth in dissimilar ways. Here, a study 198 S. Soleman et al. / Neuroscience 253 (2013) 194–213 demonstrated that Sema5A possesses a bifunctional guidance role which is dependent on HSPG and CSPG interaction (Kantor et al., 2004). This has been shown to be mediated by the thrombospondin repeats of Sema5A physically interacting with the GAG portion of these proteoglycans. HSPGs expressed on the surface of extending fasciculus retroflexus axons mediate the permissive effects of Sema5A. In contrast, CSPGs have been shown to convert Sema5A-induced axon attraction of extending axons into repulsion (Kantor et al., 2004). Thus, this suggests the Sema5A thrombospondin repeat domains play important roles in both the attractive and inhibitory functions via interactions with different types of GAGs. Importantly, this also sheds light on the role of CSPGs and how they exert their inhibitory influences, which at least is in part by modulating semaphorin function. Furthermore, it has also been identified that class 4 semaphorins (Sema4) represent important regulators of glutamatergic and GABAergic synapse development (Paradis et al., 2007). It was found in primary hippocampal neurons that RNAi constructs targeting Sema4B affected the frequency and amplitude of AMPA receptor-mediated mEPSCs as well as the density of AMPA receptor containing synapses. This suggests a role for Sema4B in glutamatergic synapse development. Additionally, knockdown of Sema4B, but not Sema4D, also reduced the density of the postsynaptic scaffolding protein PSD-95 puncta, suggesting Sema4B is preferentially required for regulating postsynaptic development and maturation (Paradis et al., 2007). Collectively, these studies demonstrate the differential effects of semaphorins on axonal growth and synapse formation. It also reveals a potential mechanism for the restriction of developmental plasticity in PNNs and that the repulsive effects may involve Sema3A. Recently, there has been an exploration of a diffusible homeobox transcription factor that is important for the maturation and maintenance of PNNs. It has been found that orthodenticle homeobox protein 2 (Otx2), produced in the retina and in the choroid plexus, binds with high affinity to chondroitin6-sulfate in PNNs (Beurdeley et al., 2012; Spatazza et al., 2013). These findings show that Otx2 recognizes particular GAG sulfation patterns on PNNs, binding particularly to CS-E. Recent evidence has suggested a developmental increase in the 4-sulfation/ 6-sulfation ratio of CSPGs may be required for the accumulation of Otx2 (Miyata et al., 2012). Therefore, the progressive refinement of the PNN sulfation profile may in part cause how PV cells recognize Otx2. Cells that are found to internalize Otx2 are restricted to relay centers along the primary visual pathway in neonates and specifically localized to PV cells (Nothias et al., 1998; Sugiyama et al., 2008). The expression of Otx2 is undetectable in the mouse visual cortex around postnatal week 3; however expression becomes markedly increased around postnatal week 4, a time associated with the critical period (Sugiyama et al., 2008). It has been found that Otx2 mediates a bidirectional effect, where conditional Otx2 deletion decreases PV cell maturation and early Otx2 infusion increases PV cell expression of molecular components as well as PNN formation (Sugiyama et al., 2008). The termination of plasticity in cells that acquire PNNs has been linked to sustained Otx2 internalization and the successive accumulation of this homeoprotein accelerates the maturation of PNNs. Blockade or loss of Otx2 in adulthood leads to loss of PNNs and a reactivation of plasticity until both PNN and Otx2 levels recover (Beurdeley et al., 2012). Thus, Otx2 may serve as a regulator of plasticity during development and adulthood which not only opens the critical period but also leads to its premature closure. Importantly, the threshold levels of Otx2 in PV cells which reflect the degree of plasticity could be valuable targets for plasticity-inducing treatments. Finally, it has been shown that perturbing the inhibitory properties of CSPGs in the post-spinal cord injury (SCI) environment with ChABC and growth factors can enhance the regenerative response of endogenous spinal neural precursor cells after contusive SCI (KarimiAbdolrezaee et al., 2012). Treatment with ChABC and growth factors increased proliferation of neural precursor cells and led to increased differentiation into oligodendroglial lineage, reducing the generation of new astrocytes and reducing proliferating macrophages and microglia after SCI. These results provide evidence that the microenvironment after SCI can be altered by targeting CSPGs to enhance the regenerative potential of neural precursor cells by reducing inflammation and facilitating the prerequisite for remyelination (KarimiAbdolrezaee et al., 2012). TARGETING THE EXTRACELLULAR MATRIX IN NEUROLOGICAL DISORDERS The ECM molecules play both the causal and modulatory roles in pathogenesis of various CNS diseases and determine the outcome following injuries. Mutations in genes encoding ECM molecules, such as leucine-rich, glioma-inactivated 1 (LGI1) and collagen type IV, alpha 1 can induce epilepsy and vascular dementia. On the other hand, secondary alterations of ECM accompanying diverse brain diseases modulate plasticity and affect regeneration. Injury to the mature mammalian CNS in spinal cord injury, stroke and traumatic brain injury results in permanent and debilitating consequences, largely due to the failure of neurons to re-form lost connections after injury. A number of potent growth-inhibitory molecules have been identified in the ECM which restrict this structural plasticity and are either present in the environment or substantially up-regulated following CNS injury. Furthermore, studies have shown alterations in ECM expression and composition are linked to other CNS diseases such as Alzheimer’s disease, epilepsy and schizophrenia, and suggest they may play a part in their pathogenic role. A number of strategies to promote anatomical recovery have targeted or manipulated mechanisms underlying the influence of the ECM following CNS disorders. Here, we focus on methods S. Soleman et al. / Neuroscience 253 (2013) 194–213 used to manipulate the ECM to enhance synaptic plasticity and recovery after CNS disorders. TRAUMATIC CENTRAL NERVOUS SYSTEM INJURY Traumatic injury to the adult CNS produces tissue damage, disruption to long axonal projections and the degeneration of denervated and damaged neurons. The failure of functional regeneration is attributed to a number of factors, particularly to the failure of axon regeneration and the low level of plasticity in the adult CNS. A large body of evidence demonstrates that the extrinsic environment plays a critical role in influencing axonal growth. One of the main physical and molecular barriers to regenerating axons is the formation of a glial scar following CNS injury. The formation of a glial scar is a neural wound healing response that prevents the further spread of damage to uninjured parts of the nervous system and controls the inflammatory process (Faulkner et al., 2004; Sofroniew, 2009). However, it can act to physically block advancing growth cones near the lesion site due to the dense meshwork of reactive glial cells, and molecules present in the ECM of the glial scar can act to actively inhibit axonal growth (Bradbury and Carter, 2010). This leads to abortive growth and axons display the characteristic morphology of retracted axons with reactive end bulbs, dystrophic endings and axonal tips retracting away from the initial lesion (Ramon y Cajal, 1928). The glial scar forms through the involvement of astrocytes, meningeal cells, microglia and oligodendrocyte precursor cells (OPCs), which are activated during different times in the inflammatory process. The main axonal growth-inhibitory molecules up-regulated in the glial scar are CSPGs and increased levels of CSPGs can persist for several months after CNS injury (Asher et al., 2001). It has been previously demonstrated that reactive astrocytes in vitro upregulate CSPGs and exert CS-GAG dependent inhibition of axonal elongation of DRG neurons (SmithThomas et al., 1995), and that OPCs also contribute to CSPG production to inhibit neuronal growth (Chen et al., 2002). Additionally, further molecules associated with CSPGs are involved in regulating regeneration. These include chemorepellent semaphorins that are secreted by meningeal fibroblasts invading the lesion core (Pasterkamp et al., 1999). These observations demonstrate that neuronal growth is constrained after injury and that this is partly associated with CSPGs and other related molecules expressed either in the reactive glial environment or after postnatal development. It is noteworthy, however, that glial response to trauma is highly heterogeneous and can also lead to reactive synaptogenesis in the CNS (Lo et al., 2011; Tran et al., 2012). It is activated by extracellular ATP through the activation of P2Y receptors and results in expression and secretion of astroglial ECM molecules, thrombospondins, which have been shown to promote formation of presynaptically active but are postsynaptically silent synapses through interaction with their neuronal receptors, calcium channel subunit a2d-1 199 and neuroligin 1 (Christopherson et al., 2005; Eroglu et al., 2009; Xu et al., 2010). Pharmacological blockade of astrocyte function, purinergic receptors, extracellular signal-regulated kinase, and thrombospondins significantly reduced or eliminated reactive synaptogenesis, suggesting that purinergic signaling, by regulating thrombospondin expression, may play an important role during central nervous system repair. TARGETING THE ECM AND GLIAL SCAR AFTER SPINAL CORD INJURY After SCI, reactive astrocytes and OPCs greatly upregulate high levels of CSPGs which exert a CS-GAG dependent inhibitory effect on axonal growth (Asher et al., 2000). Silver and colleagues demonstrated in vivo impediments to axon regeneration from CSPGs in the adult CNS, where micro-transplanted DRG neurons grew axons until encountering the CSPG-rich scar tissue surrounding the lesion after SCI. Subsequently, axonal growth ceased and the presence of dystrophic growth cones was evident (Davies et al., 1999). A method to eliminate this CSPG barrier to axonal growth and encourage plasticity is by the application of ChABC. ChABC is an enzyme derived from the bacteria Proteus vulgaris, and degrades the inhibitory CS-GAG side-chains from the CSPG protein core (Crespo et al., 2007). The use of ChABC in vitro first led to evidence that the CS-GAG side-chains represent a major inhibitory component of the CSPGs. It was shown that myelin-free plasma membranes from injured CNS tissue were less inhibitory to neurite outgrowth following ChABC treatment (Bovolenta et al., 1993). Furthermore, it was shown that ChABC treatment led to significant increases in neurite length in embryonic retinal neurons explanted on gliotic tissue formed in vivo (McKeon et al., 1995). Collectively, ChABC treatment has been shown to increase neurite extension across a number of growth-inhibitory culture models in vitro, it has been shown to promote growth permissiveness in inhibitory astrocytic cell lines (Smith-Thomas et al., 1994), oligodendrocyte lineage cells (Asher et al., 2002) and across Schwann cell/astrocyte boundaries in a dorsal root entry zone model (Grimpe et al., 2005). More recently, ChABC treatment has been shown to increase the number of corticospinal tract (CST) axons crossing the junction between the brain cortex and spinal cord in an organotypic coculture (Nakamae et al., 2009). These observations that in vitro degradation of CS-GAG sidechains using ChABC can be growth permissive has led to a number of in vivo studies incorporating the use of ChABC following CNS injury. It was first demonstrated by Lemons et al. that ChABC treatment applied to contusion injured animals could degrade CSPGs at injury sites in the spinal cord, suggesting this treatment as a potential therapeutic approach to enhance axonal growth in vivo (Lemons et al., 1999). Subsequently, it was shown that ChABC treatment enabled dopaminergic nigrostriatal axons to successfully regenerate back to their targets following unilateral nigrostriatal axotomy lesions (Moon et al., 200 S. Soleman et al. / Neuroscience 253 (2013) 194–213 2001). This led to the effects of ChABC being evaluated in a number of CNS models of injury. The most widely studied effects of ChABC treatment in vivo has been in rodent models of SCI. Bradbury et al. were the first to demonstrate ChABC delivery following a dorsal column injury could promote regeneration of severed ascending sensory and descending CST fibers. This was also associated with the restoration of postsynaptic activity below the lesion site and recovery of locomotor and proprioceptive function (Bradbury et al., 2002). Since these findings many other studies have demonstrated beneficial effects and functional recovery of ChABC treatment following SCI (Caggiano et al., 2005; Huang et al., 2006; Tester and Howland, 2008; Garcia-Alias et al., 2009; Wang et al., 2011). A study demonstrated intrathecal ChABC treatment improved locomotor function and bladder function following more clinically applicable models of both moderate and severe spinal compression injuries (Caggiano et al., 2005). The effects of ChABC on axonal regeneration were not assessed in this study; however another study compared CST regeneration between hemisected and contused spinal injuries in adult rats (Iseda et al., 2008). It was shown CSPG immunoreactivity remained high in contused animals for at least 49 days in comparison to 18 days in hemisected animals. Following a single intraspinal injection of ChABC, CST axons in the hemisection model were able to grow around the lesion site, whereas most CST axons retracted in the contusion model (Iseda et al., 2008). This may suggest more severe contusion injuries may either require longer infusions of ChABC or combination treatments alongside ChABC. For this reason various methods have been constructed to allow stable and sustained ChABC release. Hydrogel based systems have been developed to ensure sustained local delivery of ChABC in vivo (Hyatt et al., 2010; Lee et al., 2010). This avoids the use of repeated injections or local infusions of the drug over a period of days to weeks, thus overcoming invasive, infection-prone methods and making it more clinically viable to ensure spatial- and temporalcontrolled delivery that is confined to the targeted site. Normal ChABC can be detected in the CNS over three weeks after infusion (Chau et al., 2004), however it has now been demonstrated that thermostabilized ChABC remains active at 37 °C for up to 4 weeks in vitro and CSPG levels remained low for up to 6 weeks after SCI in vivo in comparison to unstabilized ChABC (Lee et al., 2010). Furthermore, the implantation of a fibrin gel containing ChABC adjacent to the SCI site revealed low CSPG levels 3 weeks after injury and showed better effectiveness in comparison to intraspinal injections of ChABC (Hyatt et al., 2010). Another method of ChABC delivery is gene therapy, which produces high-levels and long-lasting local expression of a transgene with a single injection. Furthermore, expression could also be produced in the glia that produce the inhibitory CSPGs and in the neurons that are affected by them. Recently, vectors were produced for expression of modified chondroitinase gene to allow ChABC secretion from mammalian cells and functional enzyme production (Zhao et al., 2011). It was demonstrated that these ChABC vectors lead to extensive digestion both locally and from long-distance axon projections, which lasted more than 4 weeks in vivo. Importantly, it reduced axonal die-back and promoted sprouting of corticospinal axons after dorsal column injury (Zhao et al., 2011), similar to results from intermittent intrathecal infusions of ChABC (Bradbury et al., 2002). Finally and more recently, electrospun collagen nanofibers have incorporated ChABC via microbial transglutaminasemediated crosslinking (Liu et al., 2012). Bioactive ChABC was released from collagen scaffolds for at least 32 days in vitro; however its efficiency in vivo has yet to be determined. Together, these methods of administering ChABC can facilitate minimally invasive and sustained local delivery as well as effectively degrade CSPGs over long periods which may be required in more severe CNS injuries. Studies have also shown ChABC can influence rewiring of intact fibers and promote collateral sprouting from these pathways. Barritt et al. demonstrated ChABC promoted robust sprouting of injured corticospinal axons in addition to intact serotonergic and primary afferents following dorsal column injury. Interestingly, ChABC did not induce sprouting from spinal fibers in uninjured animals, suggesting that both CSPG degradation and denervation from injury are required to promote sprouting. Other studies have also observed uninjured fibers successfully innervating areas partially denervated by injury following ChABC treatment in rats (Tropea et al., 2003; Massey et al., 2006; Galtrey et al., 2007; Massey et al., 2008; Garcia-Alias et al., 2009). In particular, Massey et al. demonstrated functional connectivity from spinal projections undergoing collateral sprouting into the partially denervated brainstem nuclei following cervical dorsal column injury and ChABC treatment. Anatomical tracing revealed significantly more labeled afferents sprouting and occupying a greater area of the ipsilateral cuneate nucleus. Importantly, electrophysiological receptive field mapping revealed the sprouting afferents had made functional connections where forelimb stimulation showed an increased receptive field in the ipsilateral cuneate nucleus (Massey et al., 2006). More recently, this has been extended to squirrel monkeys with ChABC treatment showing similar results (Bowes et al., 2012). It has been suggested that the functional collateral sprouting was due to the digestion of PNNs by ChABC, which would render the CNS more plastic by allowing the formation of new connections. Promisingly, a recent SCI study has also shown that digestion of PNNs upregulated around phrenic motor neurons in conjunction with a peripheral nerve graft resulted in regeneration of serotonergic, bulbospinal axons and the plasticity of spared tracts (Alilain et al., 2011). This was also accompanied with considerable diaphragmatic recovery and restoration of function was eliminated once the initial graft bridge was transected, demonstrating recovery was mediated through the regeneration and plasticity of axonal pathways. S. Soleman et al. / Neuroscience 253 (2013) 194–213 Plasticity can also be driven by environmental stimulation or rehabilitation (Biernaskie and Corbett, 2001; Komitova et al., 2006). A study investigated both ChABC-induced plasticity and rehabilitation treatment, as it is known rehabilitation can enhance the recovery process (Biernaskie and Corbett, 2001; Girgis et al., 2007). In this study, animals were trained on task specific rehabilitation for skilled paw function along with ChABC treatment which was found to synergistically enhance skilled motor function and CST sprouting following cervical dorsal funiculus lesions. ChABC alone was shown to promote anatomical sprouting, but recovery of skilled paw function was only evident in the combination group (Garcia-Alias et al., 2009). This suggests that while ChABC enhances spinal plasticity, the addition of task specific rehabilitation strengthens good functional connections and perhaps helps remove ‘‘incorrect’’ ones. Collectively, these studies demonstrate manipulations in the ECM and PNNs using ChABC can also increase plasticity of intact fibers and promote functional recovery after SCI. TARGETING THE ECM AND GLIAL SCAR AFTER STROKE After ischemic stroke a number of growth-inhibitory molecules are differentially expressed within the periinfarct region. In particular, a small area immediately adjacent to the infarct core that incurs partial cell death has a substantial increase in CSPGs produced by reactive astrocytosis (Katsman et al., 2003). The upregulated CSPGs are comparable to other CNS lesions, which include neurocan, phosphacan, brevican and NG2 (McKeon et al., 1999; Asher et al., 2000; Jones et al., 2003; Matsumoto et al., 2008). In particular, versican is considerably up-regulated around the infarct by OPCs, a cell type associated with CNS scar formation (Fawcett and Asher, 1999; Asher et al., 2002; Carmichael et al., 2005). Interestingly, in areas more distant from the infarct there is a reduction in the number of these inhibitory CSPGs particularly in the number of PNNs (Katsman et al., 2003; Hobohm et al., 2005a; KaretkoSysa et al., 2011), supporting the idea that part of the peri-infarct region possesses an environment for poststroke axonal sprouting (Carmichael, 2006). Recently, the effects of manipulating CSPGs using ChABC treatment have been investigated after stroke in vivo (Hill et al., 2012; Soleman et al., 2012). This was first demonstrated in an elderly model of ischemic stroke (Soleman et al., 2012), as age is known to be the most important non-modifiable risk factor for stroke (Rothwell et al., 2005). It was demonstrated that delayed intraspinal ChABC treatment was able to promote forelimb sensorimotor recovery in aged rats. ChABC was able to enhance collateral sprouting of the corticospinal tract from the contralesional hemisphere and functional recovery is assumed to be attributed to the plasticity of spinal circuitry as ChABC did not promote neuroprotection. ChABC was also found to degrade PNNs present around neurons in the spinal cord which may reactivate plasticity (Soleman et al., 201 2012). The brain’s response to injury is known to alter during aging (Esiri, 2007) with neuroplasticity and neurophysiology changing in aged subjects (Badan et al., 2003; Ward, 2005). Importantly, these findings provide further evidence that ChABC can promote recovery by increasing spinal cord plasticity in an elderly CNS system after ischemic stroke and are consistent with previous studies showing ChABC-mediated plasticity in the adult spinal cord (Galtrey et al., 2007; Cafferty et al., 2008; Tom and Houle, 2008). Furthermore, the effects of ChABC and the growthstimulating HSPG glypican were tested in the periinfarct region after ischemic stroke (Hill et al., 2012). Treatment involved direct infusion into the infarct cavity, where it was found to reduce the thickness of the astrocytic glial scar and increase microtubule-associated protein 2 immunoreactivity in the peri-infarct region. Additionally, it was shown ChABC or glypican treatment was able to promote motor recovery and these improvements may be related to the changes in growth factor expression and neuritogenesis (Hill et al., 2012). Collectively, these studies demonstrate that targeting CSPGs either neighboring the infarct region or in more distal portions of the CNS after stroke can promote functional recovery and propose ChABC as a therapeutic candidate for ischemic stroke. AMBLYOPIA AND DISORDERS OF THE VISUAL SYSTEM The anatomical and physiological organization of the visual cortex in mammals is immature at birth, and gradually develops in the first weeks and months of postnatal life. During this period, specific patterns of neuronal activity are generated from visual stimulation and other brain activities to contribute to visually guided behavior and visual perception (Espinosa and Stryker, 2012). Adult specific neuronal circuitry is established after substantial structural plasticity through strengthening, remodeling and eliminating synaptic connections. Thus, vision-associated neurons are eventually tuned via the quantity and quality of visual stimuli received through both eyes. Shortly after birth, the anatomical representation and physiology of the visual cortex can be altered in monocular deprivation (via eyelid suture or mask rearing) (Hubel et al., 1976), but these cortical rearrangements are restricted to early developmental stages during the critical period, and ocular dominance plasticity in adulthood is limited. During this period, damage or closure of one eye results in the expansion of the ocular dominance columns serving the open eye, and subsequently both cortices become more responsive to the open eye and reduced in the deprived eye. These changes occur in human children if a cataract or squint is present, leading to amblyopia, in which vision through the deprived eye is poor with low contrast sensitivity and loss of depth perception (Berardi et al., 2003). Importantly, if the visual defect is not corrected before the end of the critical period (before 5 years in humans) the vision will not recover if later corrected. 202 S. Soleman et al. / Neuroscience 253 (2013) 194–213 The closure of the critical period is associated with the up-regulation of CSPGs and GAG sulfation pattern changes in the visual cortex and with the formation of PNNs around PV interneurons (Pizzorusso et al., 2002). As CSPGs are important in maintaining stability, the disruption of CSPG-rich PNNs with ChABC renders the CNS more plastic and re-opens the critical period (Pizzorusso et al., 2002; Corvetti and Rossi, 2005). This was first shown in a study in the visual system of monocular deprived adult rats. ChABC was injected into the visual cortex and stimulated a shift in ocular dominance to the non-deprived eye, an event only seen during the critical period of development (Pizzorusso et al., 2002). Furthermore, it was later shown ChABC instilled complete recovery of ocular dominance, visual acuity and dendritic spine density following monocular deprivation in adult rats (Pizzorusso et al., 2006). Importantly, a study in which PNNs were greatly attenuated in mice lacking the cartilage link protein Crtl1 demonstrated that plasticity in the visual and somatosensory system was strongly enhanced in these mutants and similar to ChABC treatment (Carulli et al., 2010). Overall, CSPG levels and their pattern of glycan sulfation remained unchanged in knockout animals in comparison to wild type, therefore only the recruitment of a small proportion of these CSPGs were affected (around 2%). This study incorporated two adult CNS models (Pizzorusso et al., 2002; Massey et al., 2006) previously used to test the effects of ChABC on plasticity. In Crtl1 deficient mice, a shift in ocular dominance was evident following monocular deprivation, in addition to sprouting of residual axons into denervated regions of the cuneate nucleus following dorsal column transection (Carulli et al., 2010). These results were similar to ChABC and therefore suggest ChABC disrupts PNNs to reactivate ocular dominance plasticity. Recently, monocular deprivation was induced in cats from the start of the critical period and the functional architecture of the visual cortex was assessed by optical imaging after ChABC administration (Vorobyov et al., 2013). Digestion of CSPGs promoted moderate recovery of visual cortical responses in the hemisphere contralateral to the deprived eye. However, visually evoked potentials were largely absent through the deprived eye in both treated and untreated cortical hemispheres (Vorobyov et al., 2013) suggesting that ChABC alone was not enough to enable complete functional recovery in this model. Therefore, it may suggest that combination therapy is required for more effective recovery, such as ChABC with visual stimulation requiring binocular interaction (Li et al., 2009). It has already been shown that environmental enrichment alone restores visual acuity after long-term monocular deprivation through decreased PNN density in the visual cortex, increased sensory-motor stimulation and reduced GABAergic inhibition (Sale et al., 2007). Collectively, this demonstrates that both structural changes in the ECM and visual stimulation are important for enhancing plasticity after monocular deprivation and future studies combining these strategies would be of interest. The use of ChABC has also been studied after retinal damage. Combination therapy using both ChABC and brain-derived neurotrophic factor (BDNF) was shown to markedly enhance the plasticity and sprouting of undamaged retinal afferents into the denervated superior colliculus following a partial retinal lesion in comparison to the separate administration of these treatments (Tropea et al., 2003). It is known that ChABC treatment increases activation of the extracellular-signal-regulated kinase (ERK) pathway (Carter et al., 2008). Interestingly, a recent study has found that the ERK 1 and 2 pathways modulate experience-dependent gene transcription, synaptic plasticity and consequently visual recognition memory (Silingardi et al., 2011). Elevated levels of ERK 2 activation is paralleled by an enhanced performance in visual recognition memory and increased synaptic plasticity in the perirhinal cortex, whereas pharmacological blockade of ERK activation impaired long-term recognition memory in adult mice (Silingardi et al., 2011). Thus the effects of synaptic plasticity through this signalling pathway may also be an important step in how ChABC mediates its role in plasticity and repair after injury. Furthermore, therapeutic strategies aimed at adjusting intercellular transfer of Otx2 into PV circuits have proved successful in the visual system. A peptide mimicking the Otx2-GAG binding site to block Otx2 transfer in the visual cortex rescued cortical acuity in amblyopic mice and restored visual cortical plasticity in mature mice. It was found to antagonize endogenous Otx2 internalization, down-regulate PV expression and WFA binding sites and thus to reactivate plasticity in the binocular visual cortex (Beurdeley et al., 2012). EXTRACELLULAR MATRIX AND EPILEPSY Epilepsy is a disease characterized by recurrent seizures, which can cause motor, sensory, cognitive, psychic or autonomic disturbances. Seizures themselves are the clinical manifestation of an underlying transient abnormality of neuronal activity, and the phenotypic expression of each seizure is determined by the point of origin of the hyperexcitability and its degree of spread in the brain. As the ECM regulates numerous aspects of neural development and plasticity, it is not surprising that mutations in ECM molecules are associated with some forms of epilepsy (Dityatev, 2010). Moreover, seizures have been shown to modulate the expression of many ECM molecules and extracellular proteases. The resulting pathological remodelling of ECM may trigger numerous secondary long-term functional and structural changes in the CNS that could determine the progression of epileptogenesis (Fig. 2). Early studies revealed changes in multiple components of PNNs, including tenascin-C, tenascin-R, neurocan and phosphacan following seizures (reviewed in (Dityatev and Fellin, 2009). A recent study highlights the dramatic and persistent reduction in aggrecan expression in PNNs, which remained attenuated even 2 months after status epilepticus (McRae et al., 2012). S. Soleman et al. / Neuroscience 253 (2013) 194–213 203 Fig. 2. The ECM-mediated mechanisms of epileptogenesis. The cascade of molecular and functional alterations (pink) is triggered either by mutations in ECM andrelated molecules or by acute brain insults (gray). Several potential ECM-based anti-epileptogenic and anti-epileptic treatment strategies (green) are envisaged but remain to be verified. The decrease in aggrecan expression in PNNs was preceded by a decrease in hyaluronan and hyaluronan synthase 3, and proteoglycan link protein 1 (HAPLN1) which serves to stabilize the connection between CSPGs, including aggrecan, and hyaluronan. Disorganization of PNNs could contribute to the generation of a permissive environment for neuronal reorganization during epileptogenesis (McRae et al., 2012), analogous to the promotion of spinal cord regeneration after administration of chABC (Bradbury et al., 2002). However, PNN components have multiple additional functions and their contribution to epileptogenesis remains to be determined. Noteworthy is the observation that acute digestion of chondroitin sulfates leads to impaired LTP and LTD in CA3–CA1 synapses (Bukalo et al., 2001). Mice deficient in tenascin-R show abnormal PNNs, impaired perisomatic inhibition and GABAergic innervation in the CA1 region and opposite changes in the dentate gyrus, resulting in impaired LTP in both regions (Bukalo et al., 2007; Morellini et al., 2010). Furthermore, these mutants have widespread astrogliosis and retarded kindling (Hoffmann et al., 2009), highlighting that manipulation of the ECM could have beneficial anti-epileptogenic effects. Some of the extracellular secreted molecules also accumulate in synapses. Among these is LGI1. In humans, mutations in LGI1 cause autosomal dominant lateral temporal epilepsy or autosomal dominant partial epilepsy with auditory features during the onset of childhood/adolescence and a benign evolution (Nobile et al., 2009). Multiple LGI1 mutations have been described in familial and sporadic lateral temporal epilepsy patients. The mutations are distributed throughout the gene and are mostly missense mutations occurring in both the N-terminal leucine rich repeat and C-terminal epitempin LGI1 domains, which appear to prevent secretion of mutant proteins or their interactions (Nobile et al., 2009). In addition, auto-antibodies directed against LGI1 have been shown to underlie limbic encephalitis and temporal lobe seizures (Irani et al., 2010). A recent study indicates that LGI1 interconnects presynaptic disintegrin and metalloproteinase domain-containing protein 23 (ADAM23) to postsynaptic ADAM22 at the synaptic cleft (Fukata et al., 2010). The LGI1 complex also contains postsynaptic scaffolding proteins (postsynaptic density proteins 95 and 93, and the synapse-associated protein 97), presynaptic scaffolding proteins (Ca2+/calmodulinactivated serine-threonine kinase and Lin7), and presynaptic K+ channels (Kv1.1, Kv1.4 and Kvb1 subunits) (Schulte et al., 2006). Loss of LGI1, ADAM22 or ADAM23 results in lethal epilepsy in mice (Sagane et al., 2005; Owuor et al., 2009; Fukata et al., 2010), highlighting the vital role of the LGI1 complex in preventing epileptogenesis. During the last decade, multiple data also indicate an involvement of extracellular proteolysis in the pathogenesis of epilepsy. Particularly convincing is the evidence for a role of the matrix metalloproteinase-9 (MMP-9) (Lukasiuk et al., 2011). The available data show MMP-9 robust activation by seizure-evoking stimuli (Zhang et al., 1998; Szklarczyk et al., 2002), decreased susceptibility to pentelenetetrazol kindling in MMP-9 knockout mice and increased susceptibility in transgenic rats with neuronal overexpression of autoactivating MMP-9 (Wilczynski et al., 2008). The observations that aberrant synaptic plasticity contributes to epileptogenesis and that MMP-9 is a key molecule for synaptic plasticity (Nagy et al., 2006; Okulski et al., 2007; Huntley, 2012), acting via b1 integrins (Nagy et al., 2006; Kim et al., 2009; Michaluk et al., 2009; Michaluk et al., 2011), indicate that MMP-9 could play a crucial role in epileptogenesis through a similar mechanism. Molecular profiling studies have shown that the expression of urokinase-type plasminogen activator (uPA) was most up-regulated during epileptogenesis following status epilepticus (Lukasiuk et al., 2011). The uPA receptor knockout mice have epilepsy that is associated with abnormal migration of GABAergic interneurons in the frontal cortex and the hippocampus. 204 S. Soleman et al. / Neuroscience 253 (2013) 194–213 On the other hand, patients with Rolandic epilepsy and speech impairment or bilateral perisylvian polymicrogyria have a mutation in SRPX2 (Sushi-repeat Protein, X-linked 2) gene encoding SRPX2 protein that is one of the ligands of uPAR (Royer-Zemmour et al., 2008). These studies suggest that the uPA-dependent mechanisms might contribute to epileptogenesis. Another important ectoproteinase is ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin motifs). ADAMTS4 processes all members of the lectican protein family such as aggrecan, brevican, neurocan and versican and thus has the potential to be a major player in cleavage of PNNs and for broader ECM remodeling in the brain (Zimmermann and DoursZimmermann, 2008; Gundelfinger et al., 2010). This process is very likely to be important to permit restricted and local structural plasticity in the brain required for synapse formation and elimination during epileptogenesis. Interestingly, after kainic acid injection, brevican cleavage by ADAMTS4 is strongly increased in the hippocampus, various thalamic nuclei and in the basolateral amygdaloid nuclei (Yuan et al., 2002), correlating with up-regulation of ADAMTS4 mRNA (Yuan et al., 2002). However, the functional consequences and relevance of this regulation for epilepsy has yet to be verified. In summary, we suggest that at early stages of epileptogenesis, it could be beneficial to prevent neural network rewiring via the inhibition of ECM remodeling, for instance by targeting ectoproteases or by delivery of ECM protecting cross-linking reagents. In contrast, at later stages of epileptogenesis or during established epilepsy, when hyperexcitable networks have already been formed, transient application of ECM degrading enzymes might enable homeostatic plasticity and/or network rewiring, thus permitting global ‘‘normalization’’ of the network activity. The major challenge will be to direct reactivated structural plasticity in the ‘‘right’’ direction. This could possibly be achieved through the co-administration of factors (e.g. BDNF) which would promote the formation and activity of GABAergic synapses; or with the use of conventional anti-epileptic drugs and rehabilitation training to transiently support the normalization of network activity and thus aid the reexpression of ‘‘healthy’’ ECM capable for long-term stabilization of the rewired networks. EXTRACELLULAR MATRIX AND ALZHEIMER’S DISEASE One of the most common and intensively studied neurodegenerative diseases is Alzheimer’s disease (AD). It leads to cognitive impairment, neuronal loss and severe brain dystrophy at late stages. Mostly, AD is diagnosed in the people over 65 years of age (Brookmeyer et al., 1998), although less prevalent onset of the disease can occur much earlier. Well known AD hallmarks are the protein aggregations containing Ab peptides (amyloid plaques in brain parenchyma and amyloid deposits around blood vessels, i.e. cerebral amyloid angiopathy) and intercellular aggregations containing hyperphosphorylated Tau protein (termed as neurofibrillary tangles), which are typically found in postmortem brains of AD patients. There are several hypotheses of AD pathogenesis that are related to the mentioned hallmarks. Intercellular Tau tangles impair the neuronal transport system, which results in malfunction of neuronal communication and could lead to cell death (Iqbal et al., 2005; Chun and Johnson, 2007). Amyloid plaques cause the generalized neuroinflammation (Wenk, 2003). Ab solvable oligomers, termed as amyloid-derived diffusible ligands (ADDLs), bind to the various specific neuronal receptors to impair the synaptic activity and disrupt neuronal communication (Lacor et al., 2007; Lauren et al., 2009). The initial studies of PNN alterations in AD reported the severe reduction of PNN staining in the brains of AD patients (Kobayashi et al., 1989; Leuba et al., 1998; Bruckner et al., 1999; Baig et al., 2005), which later turned out to be an artifact of tissue decomposition (Hobohm et al., 2005b; Morawski et al., 2012). Recent data published by Morawski et al. (2012) did not reveal any alterations in PNN number or distribution in AD patients compared with healthy controls. The group has also investigated whether the composition of PNNs was different in the close proximity to amyloid plaques. They have discovered that the amount of hyaluronic acid was increased in PNNs which were attached to the coronal or marginal zone of the plaques; however there were no expression of the PNNs in the plaque core. Several studies have also indicated that both interneurons and pyramidal cells ensheathed in PNNs were devoid of Tau pathology, even in the areas severely affected by Tau tangles (Bruckner et al., 1999; Hartig et al., 2001; Morawski et al., 2010, 2012). These studies suggest that PNNs could have a neuroprotective function in AD, which is in line with the results of an in vitro analysis of Ab toxicity (Miyata et al., 2007). Application of Ab(1–42) to rodent primary neuronal cultures caused neuronal death of neurons not associated with PNNs, while the neurons expressing PNNs were unaffected. However, if PNNs were predigested with ChABC, these neurons began dying after Ab(1–42) treatment. Other studies that have investigated the effects of neuronal stress, also revealed the neuroprotective role of PNNs. These include ironinduced oxidative stress in the human cerebellar cortex (Morawski et al., 2004), different in vitro models like excitotoxicity in cultured primary neurons of the rat (Okamoto et al., 1994) and oxygen or glucose deprivation in rat hippocampal slices (Martin-deSaavedra et al., 2011). The neuroprotective effects may be mediated by hyaluronic acid and chondroitin sulfate chains as they create a polyionic microenviroment for ensheated neurons (Bruckner et al., 1993; Hartig et al., 1999), which could isolate/protect these neurons from external stress factors, such as Ab (Miyata et al., 2007) (Fig. 3). Another possibility is that hyaluronic acid and chondroitin sulfates could stimulate anti-apoptotic protein kinase C/phosphoinositide 3-kinase (PI3K)/Akt S. Soleman et al. / Neuroscience 253 (2013) 194–213 205 Fig. 3. Perisynaptic ECM and Alzheimer’s disease. In Alzheimer’s disease, the neurons covered with PNNs do not undergo degeneration. At least their perisomatic synapses are protected by PNNs, in part possibly because the diffusible forms of Ab cannot penetrate them (1, left), which is not the case of the synapses, which are not coated with PNNs (1, right). Ab can potentially bind to the various types of cell surface or secreted HSPGs (2). The amyloid plaques contain various types of HSPGs including the shed HSPGs derived from the cell surface molecules (3). HSPGs in the amyloid plaques form the ‘‘pathogenic ECM’’, which restrict proteinases from Ab cleavage and inhibits Ab clearance. HSPGs frequently serve as coreceptors for the number of different ligands. When Ab enters the synapse and potentially binds to cell surface, it generates various effects on presynaptic or postsynaptic level. For example, Ab can trigger massive rapid neurotransmitter release (4), which is followed by severe reduction of vesicle recycling (5). As the result, the affected synapse has a major reduction of synaptic vesicles and its function is impaired (Parodi et al., 2010). In addition, several and sometimes even opposite postsynaptic effects were demonstrated. Such discrepancies most likely are the result of diversity of soluble Ab forms, which are now commonly termed as Ab-derived diffusible ligands (ADDLs, 6). ADDLs can appear in monomeric and oligomeric forms, the oligomers could have various sizes or even shapes, e.g. globular or protofibrils (reviewed in Benilova et al., 2012). Thus different authors demonstrated totally opposite postsynaptic effects, for example either the inhibition of AMPA and ACh receptors (Tozaki et al., 2002; Parameshwaran et al., 2007) or enhancement of AMPA receptor currents (Tozaki et al., 2002) (7). Importantly, Ab impairs long-term potentiation (Lambert et al., 1998; Shankar et al., 2008) (8). pathway, which stimulates the production of heme oxygenase-1 as a potent antioxidant (Canas et al., 2007). In addition to their effect on survival, PNNs may shape activity of parvalbumin expressing interneurons that they surround. ChABC treatment of cultured basket cells was 206 S. Soleman et al. / Neuroscience 253 (2013) 194–213 found to increase excitability of PN-associated interneurons (Dityatev et al., 2007). Ab might have an opposite effect because some studies point out to possible impairment of GABAergic inhibition around Ab plaques (Busche et al., 2008). Injections of Ab in rats impaired network activities associated with generation of theta frequency oscillations upon visuospatial recognition test (Villette et al., 2010). The detailed analysis identified a specific reduction in bursting of the GABAergic neurons. Another study also revealed the impairment of gamma oscillations and synaptic activity mediated by parvalbumin-expressing neurons in a mouse model of AD (Verret et al., 2012). These defects are associated with the reduced expression of sodium channel subunit Nav1.1 in parvalbumin-expressing cells in both AD patients and the transgenic mouse model of AD. Furthermore, the expression of recombinant Nav1.1 could restore the proper electrophysiological characteristics in AD transgenic mice and even abrogated their memory deficits and premature mortality. Similar to the epilepsy field, extracellularly active proteinases, including MMPs, received considerable attention in AD. Although little is known about their role in remodeling of PNN or perisynaptic ECM, they have other established functions. Importantly, MMP-9 degrades Ab fibrils in vitro or in compact plaques in situ (Yan et al., 2006). Astrocytes surrounding the amyloid plaques overexpress MMP-2 and MMP-9 in a transgenic mouse model of Alzheimer’s disease (Yin et al., 2006). Breeding these mice with MMP-2 or MMP-9 knockout mice resulted in the increased levels of Ab when compared with controls. The pharmacological inhibition of MMP-2 or MMP-9 led to the same results (Yin et al., 2006). MMP-9 action could be also beneficial in AD through its a-secretase activity toward holo-amyloid precursor protein (APP) (Fragkouli et al., 2011). Moderate overexpression of MMP-9 in neurons may promote a shift to APP non-amyloidogenic versus amyloidogenic processing and slow down the progression of AD (Fragkouli et al., 2012). Apart from these positive effects MMP-2 and MMP-9 on Ab catabolism, there are multiple additional effects, as MMPs can disrupt blood–brain barrier. In particular, the negative effects of strong MMP overexpression/ overactivation can be very straightforward. The overproduction of MMPs is the part of the neuroinflammatory response to Ab. MMP-2, MMP-3 and MMP-9 are overexpressed in AD brain (Backstrom et al., 1996; Yoshiyama et al., 2000; Asahina et al., 2001; Bruno et al., 2009) and as well as in neuronal cultures and astrocytes treated with Ab (Deb and Gottschall, 1996; Yoshiyama et al., 2000; Deb et al., 2003; Li et al., 2011). In fact, Ab(1–42) can stimulate the overproduction of MMP-3, MMP-12 and MMP-13 in microglia (Ito et al., 2007) and can cause the proliferation of the microglial cell lines (Ito et al., 2005). Gene expression studies of post-mortem human brainderived microglia showed the overexpression of MMP-1, MMP-3, MMP-9, MMP-10 and MMP-12, as well as IL-1b and IL-8 upon interaction with aggregated Ab. As MMPs cleave collagens and laminin, their overactivation leads to the damage of the blood–brain barrier and basal lamina, causes the invasion of macrophages in the brain and neurodegeneration. More information on MMPs in the context of AD is provided in two recent reviews (Rosenberg, 2009; Mroczko et al., 2013). Another broad class of molecules implicated in AD are HSPGs, many members of which are ECM molecules. This protein family contains perlecan, agrin, collagen XVIII, glypicans and syndecans. All proteoglycans carry polyanionic heparan sulfate side-chains that are attached to the core protein. Glypicans and syndecans are expressed on the cell surface, but can be shed to the extracellular space. Collagen XVIII, perlecan and agrin represent extracellular matrix proteins, although there is also a transmembrane isoform of agrin that regulates dendritic filopodia formation and synapse stabilization (McCroskery et al., 2009). The association of HSPGs with all known hallmarks of Alzheimer’s disease has been intensively studied. The HSPGs were found in amyloid deposits including senile plaques and in cerebrovascular amyloid deposits, also the presence of HSPGs was associated with neurofibrillary tangles (Snow et al., 1988, 1990a, 1994b; Perry et al., 1991). All HSPG members were found in plaques: Some studies claimed agrin as the major component of the amyloid, including both dense and diffuse plaques (Donahue et al., 1999; Verbeek et al., 1999; Cotman et al., 2000; van Horssen et al., 2002a). However, glypican 1 and syndecans 1–3 are also present in both dense and diffuse plaques and also associated with tangles (Verbeek et al., 1999). A recent study suggested glypican 1 and syndecan 3 to be the major components of amyloid plaques in the Tg2576 mouse model of AD as well as in AD patients. In addition it was revealed that these HSPGs are mainly produced by activated microglia and astrocytes which surround the amyloid plaques (O’Callaghan et al., 2008). There is a controversy about the role of perlecan in AD, as some studies also claimed perlecan to be the prominent component of amyloid plaques (Snow et al., 1988, 1990a, 1994a, 1995; Snow and Wight, 1989), whereas another group did not detect it (Verbeek et al., 1999; van Horssen et al., 2002a). Collagen XVIII was also found in dense amyloid plaques and in amyloid coated vessels (van Horssen et al., 2002b). There is an evidence that HSPGs are associated with AD pathology and all family members of HSPGs can bind Ab, which raises the question of how exactly HSPGs could be involved? One aspect was revealed by the aggregation studies. Using Thioflavin T fluorometry assay, the accelerated Ab fibril formation was shown in the presence of perlecan (Castillo et al., 1997). Agrin also accelerated Ab fibril formation and even protected Ab from the proteinases (Gupta-Bansal et al., 1995; Cotman et al., 2000). Interestingly, agrin contains nine follistatinlike protease inhibitor domains, which could help to act in this particular way (Biroc et al., 1993; Groffen et al., 1998). The cooperative role of HSPG and low density lipoprotein receptor-related protein 1 (LRP1) in the endocytosis of Ab was also demonstrated by showing that either application of heparin or inhibition of LRP1 by siRNA significantly S. Soleman et al. / Neuroscience 253 (2013) 194–213 inhibited Ab cellular uptake in different cell types (Kanekiyo et al., 2011). Authors did not determine which exactly HSPG molecules were involved, so this issue and the significance of this cooperative action of LRP1 and HSPGs in AD remains to be investigated. Another interesting question is how mono- and oligomeric Ab (ADDLs) can target the synapses and impair their function. ADDL application was found to acutely suppress neuronal activity in an in vitro system (Kuperstein et al., 2010) and LTP in rodent hippocampal slices (Lambert et al., 1998; Shankar et al., 2008). Several postsynaptic effects of Ab were described (Gasparini and Dityatev, 2008). For instance, monomeric Ab(1–42) had an effect on AMPA receptors reducing the amplitude and frequencies of mEPSCs. Both Ab(1–40) and Ab(1–42) inhibit nicotinic acetylcholine receptors (Tozaki et al., 2002). Ab aggregates also had presynaptic effects, modulating the neurotransmitter release and causing the vesicular depletion in glutamatergic synapses (Parodi et al., 2010). These data are in line with reports demonstrating the Ab immunostaining being colocalized with presynaptic markers (Noguchi et al., 2009; Kuperstein et al., 2010). Also HSPGs are present at synapses of forebrain neurons, as demonstrated for agrin (Ksiazek et al., 2007), glypican 1, 4 and 6 (Litwack et al., 1998; Allen et al., 2012) and syndecan 2 (Hsueh and Sheng, 1999). Interestingly, glypican 4 deficient mice have shown the reduced recruitment of AMPA receptors into hippocampal synapses (Allen et al., 2012), indicating that glypicans are essential for the synapse formation and postsynaptic differentiation. However, the effects of Ab and ADDLs binding to HSPGs on synaptic functions remain to be investigated. In summary, targeting of HSPGs represents a promising strategy to affect aggregation and internalization of Ab. Additionally, the identification of PNN components that have a neuroprotective function in AD and the elucidation of the underlying mechanisms represent other attractive avenues of research. Acknowledgments—This work was supported by COST Action BM1001 ‘‘Brain extracellular matrix in health and disease’’ and by Ministry of Education and Science of Russian Federation, Grant for Leading Scientists, No. 11.G34.31.0012. REFERENCES Alilain WJ, Horn KP, Hu H, Dick TE, Silver J (2011) Functional regeneration of respiratory pathways after spinal cord injury. Nature 475:196–200. Allen NJ, Bennett ML, Foo LC, Wang GX, Chakraborty C, Smith SJ, Barres BA (2012) Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors. Nature 486:410–414. Asahina M, Yoshiyama Y, Hattori T (2001) Expression of matrix metalloproteinase-9 and urinary-type plasminogen activator in Alzheimer’s disease brain. Clin Neuropathol 20:60–63. Asher RA, Morgenstern DA, Fidler PS, Adcock KH, Oohira A, Braistead JE, Levine JM, Margolis RU, Rogers JH, Fawcett JW (2000) Neurocan is upregulated in injured brain and in cytokinetreated astrocytes. J Neurosci 20:2427–2438. 207 Asher RA, Morgenstern DA, Moon LD, Fawcett JW (2001) Chondroitin sulphate proteoglycans: inhibitory components of the glial scar. Prog Brain Res 132:611–619. Asher RA, Morgenstern DA, Shearer MC, Adcock KH, Pesheva P, Fawcett JW (2002) Versican is upregulated in CNS injury and is a product of oligodendrocyte lineage cells. J Neurosci 22:2225–2236. Backstrom JR, Lim GP, Cullen MJ, Tokes ZA (1996) Matrix metalloproteinase-9 (MMP-9) is synthesized in neurons of the human hippocampus and is capable of degrading the amyloidbeta peptide (1–40). J Neurosci 16:7910–7919. Badan I, Buchhold B, Hamm A, Gratz M, Walker LC, Platt D, Kessler C, Popa-Wagner A (2003) Accelerated glial reactivity to stroke in aged rats correlates with reduced functional recovery. J Cereb Blood Flow Metab 23:845–854. Baig S, Wilcock GK, Love S (2005) Loss of perineuronal net Nacetylgalactosamine in Alzheimer’s disease. Acta Neuropathol 110:393–401. Bandtlow CE, Zimmermann DR (2000) Proteoglycans in the developing brain: new conceptual insights for old proteins. Physiol Rev 80:1267–1290. Benilova I, Karran E, De Strooper B (2012) The toxic Abeta oligomer and Alzheimer’s disease: an emperor in need of clothes. Nat Neurosci 15:349–357. Berardi N, Pizzorusso T, Maffei L (2004) Extracellular matrix and visual cortical plasticity: freeing the synapse. Neuron 44:905–908. Berardi N, Pizzorusso T, Ratto GM, Maffei L (2003) Molecular basis of plasticity in the visual cortex. Trends Neurosci 26:369–378. Beurdeley M, Spatazza J, Lee HH, Sugiyama S, Bernard C, Di Nardo AA, Hensch TK, Prochiantz A (2012) Otx2 binding to perineuronal nets persistently regulates plasticity in the mature visual cortex. J Neurosci 32:9429–9437. Biernaskie J, Corbett D (2001) Enriched rehabilitative training promotes improved forelimb motor function and enhanced dendritic growth after focal ischemic injury. J Neurosci 21:5272–5280. Biroc SL, Payan DG, Fisher JM (1993) Isoforms of agrin are widely expressed in the developing rat and may function as protease inhibitors. Brain Res Dev Brain Res 75:119–129. Boggio EM, Ehlert EME, Moloney EM, Mecollari V, Fawcett JW, Verhaagen J, Pizzorusso T (2012) AAV-mediated expression of neuropilin1-Fc, a secreted receptor that inactivates semaphorin3a, enhances ocular dominance plasticity in the adult rat visual cortex. Barcelona: 8th FENS Forum of Neuroscience. Bouzioukh F, Daoudal G, Falk J, Debanne D, Rougon G, Castellani V (2006) Semaphorin3A regulates synaptic function of differentiated hippocampal neurons. Eur J Neurosci 23:2247–2254. Bovolenta P, Wandosell F, Nieto-Sampedro M (1993) Neurite outgrowth inhibitors associated with glial cells and glial cell lines. Neuroreport 5:345–348. Bowes C, Massey JM, Burish M, Cerkevich CM, Kaas JH (2012) Chondroitinase ABC promotes selective reactivation of somatosensory cortex in squirrel monkeys after a cervical dorsal column lesion. Proc Natl Acad Sci USA 109:2595–2600. Bradbury EJ, Carter LM (2010) Manipulating the glial scar: chondroitinase ABC as a therapy for spinal cord injury. Brain Res Bull 84:306–316. Bradbury EJ, Moon LD, Popat RJ, King VR, Bennett GS, Patel PN, Fawcett JW, McMahon SB (2002) Chondroitinase ABC promotes functional recovery after spinal cord injury. Nature 416:636–640. Brakebusch C, Seidenbecher CI, Asztely F, Rauch U, Matthies H, Meyer H, Krug M, Bockers TM, Zhou X, Kreutz MR, Montag D, Gundelfinger ED, Fassler R (2002) Brevican-deficient mice display impaired hippocampal CA1 long-term potentiation but show no obvious deficits in learning and memory. Mol Cell Biol 22:7417–7427. Brookmeyer R, Gray S, Kawas C (1998) Projections of Alzheimer’s disease in the United States and the public health impact of delaying disease onset. Am J Public Health 88:1337–1342. Bruckner G, Brauer K, Hartig W, Wolff JR, Rickmann MJ, Derouiche A, Delpech B, Girard N, Oertel WH, Reichenbach A (1993) 208 S. Soleman et al. / Neuroscience 253 (2013) 194–213 Perineuronal nets provide a polyanionic, glia-associated form of microenvironment around certain neurons in many parts of the rat brain. Glia 8:183–200. Bruckner G, Grosche J, Schmidt S, Hartig W, Margolis RU, Delpech B, Seidenbecher CI, Czaniera R, Schachner M (2000) Postnatal development of perineuronal nets in wild-type mice and in a mutant deficient in tenascin-R. J Comp Neurol 428:616–629. Bruckner G, Hausen D, Hartig W, Drlicek M, Arendt T, Brauer K (1999) Cortical areas abundant in extracellular matrix chondroitin sulphate proteoglycans are less affected by cytoskeletal changes in Alzheimer’s disease. Neuroscience 92:791–805. Bruno MA, Mufson EJ, Wuu J, Cuello AC (2009) Increased matrix metalloproteinase 9 activity in mild cognitive impairment. J Neuropathol Exp Neurol 68:1309–1318. Bukalo O, Schachner M, Dityatev A (2001) Modification of extracellular matrix by enzymatic removal of chondroitin sulfate and by lack of tenascin-R differentially affects several forms of synaptic plasticity in the hippocampus. Neuroscience 104:359–369. Bukalo O, Schachner M, Dityatev A (2007) Hippocampal metaplasticity induced by deficiency in the extracellular matrix glycoprotein tenascin-R. J Neurosci 27:6019–6028. Busche MA, Eichhoff G, Adelsberger H, Abramowski D, Wiederhold KH, Haass C, Staufenbiel M, Konnerth A, Garaschuk O (2008) Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer’s disease. Science 321:1686–1689. Cafferty WB, Bradbury EJ, Lidierth M, Jones M, Duffy PJ, Pezet S, McMahon SB (2008) Chondroitinase ABC-mediated plasticity of spinal sensory function. J Neurosci 28:11998–12009. Caggiano AO, Zimber MP, Ganguly A, Blight AR, Gruskin EA (2005) Chondroitinase ABCI improves locomotion and bladder function following contusion injury of the rat spinal cord. J Neurotrauma 22:226–239. Canas N, Valero T, Villarroya M, Montell E, Verges J, Garcia AG, Lopez MG (2007) Chondroitin sulfate protects SH-SY5Y cells from oxidative stress by inducing heme oxygenase-1 via phosphatidylinositol 3-kinase/Akt. J Pharmacol Exp Ther 323:946–953. Carmichael ST (2006) Cellular and molecular mechanisms of neural repair after stroke: making waves. Ann Neurol 59:735–742. Carmichael ST, Archibeque I, Luke L, Nolan T, Momiy J, Li S (2005) Growth-associated gene expression after stroke: evidence for a growth-promoting region in peri-infarct cortex. Exp Neurol 193:291–311. Carter LM, Starkey ML, Akrimi SF, Davies M, McMahon SB, Bradbury EJ (2008) The yellow fluorescent protein (YFP-H) mouse reveals neuroprotection as a novel mechanism underlying chondroitinase ABC-mediated repair after spinal cord injury. J Neurosci 28:14107–14120. Carulli D, Laabs T, Geller HM, Fawcett JW (2005) Chondroitin sulfate proteoglycans in neural development and regeneration. Curr Opin Neurobiol 15:116–120. Carulli D, Pizzorusso T, Kwok JC, Putignano E, Poli A, Forostyak S, Andrews MR, Deepa SS, Glant TT, Fawcett JW (2010) Animals lacking link protein have attenuated perineuronal nets and persistent plasticity. Brain 133:2331–2347. Carulli D, Rhodes KE, Brown DJ, Bonnert TP, Pollack SJ, Oliver K, Strata P, Fawcett JW (2006) Composition of perineuronal nets in the adult rat cerebellum and the cellular origin of their components. J Comp Neurol 494:559–577. Castillo GM, Ngo C, Cummings J, Wight TN, Snow AD (1997) Perlecan binds to the beta-amyloid proteins (A beta) of Alzheimer’s disease, accelerates A beta fibril formation, and maintains A beta fibril stability. J Neurochem 69:2452–2465. Celio MR, Blumcke I (1994) Perineuronal nets–a specialized form of extracellular matrix in the adult nervous system. Brain Res Brain Res Rev 19:128–145. Celio MR, Spreafico R, De BS, Vitellaro-Zuccarello L (1998) Perineuronal nets: past and present. Trends Neurosci 21:510–515. Chau CH, Shum DK, Li H, Pei J, Lui YY, Wirthlin L, Chan YS, Xu XM (2004) Chondroitinase ABC enhances axonal regrowth through Schwann cell-seeded guidance channels after spinal cord injury. FASEB J 18:194–196. Chen ZJ, Negra M, Levine A, Ughrin Y, Levine JM (2002) Oligodendrocyte precursor cells: reactive cells that inhibit axon growth and regeneration. J Neurocytol 31:481–495. Choi DW, Rothman SM (1990) The role of glutamate neurotoxicity in hypoxic-ischemic neuronal death. Annu Rev Neurosci 13:171–182. Christopherson KS, Ullian EM, Stokes CC, Mullowney CE, Hell JW, Agah A, Lawler J, Mosher DF, Bornstein P, Barres BA (2005) Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell 120:421–433. Chun W, Johnson GV (2007) The role of tau phosphorylation and cleavage in neuronal cell death. Front Biosci 12:733–756. Corvetti L, Rossi F (2005) Degradation of chondroitin sulfate proteoglycans induces sprouting of intact purkinje axons in the cerebellum of the adult rat. J Neurosci 25:7150–7158. Cotman SL, Halfter W, Cole GJ (2000) Agrin binds to beta-amyloid (Abeta), accelerates abeta fibril formation, and is localized to Abeta deposits in Alzheimer’s disease brain. Mol Cell Neurosci 15:183–198. Crespo D, Asher RA, Lin R, Rhodes KE, Fawcett JW (2007) How does chondroitinase promote functional recovery in the damaged CNS? Exp Neurol 206:159–171. Davies SJ, Goucher DR, Doller C, Silver J (1999) Robust regeneration of adult sensory axons in degenerating white matter of the adult rat spinal cord. J Neurosci 19:5810–5822. De Vivo L, Landi S, Panniello M, Baroncelli L, Chierzi S, Mariotti L, Spolidoro M, Pizzorusso T, Maffei L, Ratto GM (2013) Extracellular matrix inhibits structural and functional plasticity of dendritic spines in the adult visual cortex. Mol Ther 4:1484. De Wit J, De Winter F, Klooster J, Verhaagen J (2005) Semaphorin 3A displays a punctate distribution on the surface of neuronal cells and interacts with proteoglycans in the extracellular matrix. Mol Cell Neurosci 29:40–55. Deb S, Gottschall PE (1996) Increased production of matrix metalloproteinases in enriched astrocyte and mixed hippocampal cultures treated with beta-amyloid peptides. J Neurochem 66:1641–1647. Deb S, Wenjun Zhang J, Gottschall PE (2003) Beta-amyloid induces the production of active, matrix-degrading proteases in cultured rat astrocytes. Brain Res 970:205–213. Deepa SS, Carulli D, Galtrey C, Rhodes K, Fukuda J, Mikami T, Sugahara K, Fawcett JW (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. Dityatev A (2010) Remodeling of extracellular matrix and epileptogenesis. Epilepsia 51(Suppl. 3):61–65. Dityatev A, Bruckner G, Dityateva G, Grosche J, Kleene R, Schachner M (2007) Activity-dependent formation and functions of chondroitin sulfate-rich extracellular matrix of perineuronal nets. Dev Neurobiol 67:570–588. Dityatev A, Bukalo O, Schachner M (2008) Modulation of synaptic transmission and plasticity by cell adhesion and repulsion molecules. Neuron Glia Biol. 4:197–209. Dityatev A, Fellin T (2009) Extracellular matrix in plasticity and epileptogenesis. Neuron Glia Biol 4:235–247. Dityatev A, Schachner M, Sonderegger P (2010) The dual role of the extracellular matrix in synaptic plasticity and homeostasis. Nat Rev Neurosci 11:735–746. Donahue JE, Berzin TM, Rafii MS, Glass DJ, Yancopoulos GD, Fallon JR, Stopa EG (1999) Agrin in Alzheimer’s disease: altered solubility and abnormal distribution within microvasculature and brain parenchyma. Proc Natl Acad Sci USA 96:6468–6472. Dou CL, Levine JM (1994) Inhibition of neurite growth by the NG2 chondroitin sulfate proteoglycan. J Neurosci 14:7616–7628. Eroglu C, Allen NJ, Susman MW, O’Rourke NA, Park CY, Ozkan E, Chakraborty C, Mulinyawe SB, Annis DS, Huberman AD, Green S. Soleman et al. / Neuroscience 253 (2013) 194–213 EM, Lawler J, Dolmetsch R, Garcia KC, Smith SJ, Luo ZD, Rosenthal A, Mosher DF, Barres BA (2009) Gabapentin receptor alpha2delta-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis. Cell 139:380–392. Esiri MM (2007) Ageing and the brain. J Pathol 211:181–187. Espinosa JS, Stryker MP (2012) Development and plasticity of the primary visual cortex. Neuron 75:230–249. Faissner A, Pyka M, Geissler M, Sobik T, Frischknecht R, Gundelfinger ED, Seidenbecher C (2010) Contributions of astrocytes to synapse formation and maturation – potential functions of the perisynaptic extracellular matrix. Brain Res Rev 63:26–38. Faulkner JR, Herrmann JE, Woo MJ, Tansey KE, Doan NB, Sofroniew MV (2004) Reactive astrocytes protect tissue and preserve function after spinal cord injury. J Neurosci 24:2143–2155. Fawcett JW, Asher RA (1999) The glial scar and central nervous system repair. Brain Res Bull 49:377–391. Filla MS, Dam P, Rapraeger AC (1998) The cell surface proteoglycan syndecan-1 mediates fibroblast growth factor-2 binding and activity. J Cell Physiol 174:310–321. Fisher D, Xing B, Dill J, Li H, Hoang HH, Zhao Z, Yang XL, Bachoo R, Cannon S, Longo FM, Sheng M, Silver J, Li S (2011) Leukocyte common antigen-related phosphatase is a functional receptor for chondroitin sulfate proteoglycan axon growth inhibitors. J Neurosci 31:14051–14066. Fragkouli A, Papatheodoropoulos C, Georgopoulos S, Stamatakis A, Stylianopoulou F, Tsilibary EC, Tzinia AK (2012) Enhanced neuronal plasticity and elevated endogenous sAPPalpha levels in mice over-expressing MMP9. J Neurochem 121:239–251. Fragkouli A, Tzinia AK, Charalampopoulos I, Gravanis A, Tsilibary EC (2011) Matrix metalloproteinase-9 participates in NGFinduced alpha-secretase cleavage of amyloid-beta protein precursor in PC12 cells. J Alzheimers Dis 24:705–719. Frischknecht R, Heine M, Perrais D, Seidenbecher CI, Choquet D, Gundelfinger ED (2009) Brain extracellular matrix affects AMPA receptor lateral mobility and short-term synaptic plasticity. Nat Neurosci 12:897–904. Frischknecht R, Seidenbecher CI (2008) The crosstalk of hyaluronanbased extracellular matrix and synapses. Neuron Glia Biol 4:249–257. Fry EJ, Chagnon MJ, Lopez-Vales R, Tremblay ML, David S (2010) Corticospinal tract regeneration after spinal cord injury in receptor protein tyrosine phosphatase sigma deficient mice. Glia 58:423–433. Fukata Y, Lovero KL, Iwanaga T, Watanabe A, Yokoi N, Tabuchi K, Shigemoto R, Nicoll RA, Fukata M (2010) Disruption of LGI1linked synaptic complex causes abnormal synaptic transmission and epilepsy. Proc Natl Acad Sci USA 107:3799–3804. Galtrey CM, Asher RA, Nothias F, Fawcett JW (2007) Promoting plasticity in the spinal cord with chondroitinase improves functional recovery after peripheral nerve repair. Brain 130:926–939. Galtrey CM, Fawcett JW (2007) The role of chondroitin sulfate proteoglycans in regeneration and plasticity in the central nervous system. Brain Res Rev 54:1–18. Garcia-Alias G, Barkhuysen S, Buckle M, Fawcett JW (2009) Chondroitinase ABC treatment opens a window of opportunity for task-specific rehabilitation. Nat Neurosci 12:1145–1151. Gasparini L, Dityatev A (2008) Beta-amyloid and glutamate receptors. Exp Neurol 212:1–4. Girgis J, Merrett D, Kirkland S, Metz GA, Verge V, Fouad K (2007) Reaching training in rats with spinal cord injury promotes plasticity and task specific recovery. Brain 130:2993–3003. Gotting C, Kuhn J, Zahn R, Brinkmann T, Kleesiek K (2000) Molecular cloning and expression of human UDP-dXylose:proteoglycan core protein beta-d-xylosyltransferase and its first isoform XT-II. J Mol Biol 304:517–528. Grimpe B, Pressman Y, Lupa MD, Horn KP, Bunge MB, Silver J (2005) The role of proteoglycans in Schwann cell/astrocyte 209 interactions and in regeneration failure at PNS/CNS interfaces. Mol Cell Neurosci 28:18–29. Grimpe B, Silver J (2002) The extracellular matrix in axon regeneration. Prog Brain Res 137:333–349. Groffen AJ, Buskens CA, van Kuppevelt TH, Veerkamp JH, Monnens LA, van den Heuvel LP (1998) Primary structure and high expression of human agrin in basement membranes of adult lung and kidney. FEBS J 254:123–128. Gundelfinger ED, Frischknecht R, Choquet D, Heine M (2010) Converting juvenile into adult plasticity: a role for the brain’s extracellular matrix. Eur J Neurosci 31:2156–2165. Gupta-Bansal R, Frederickson RC, Brunden KR (1995) Proteoglycan-mediated inhibition of A beta proteolysis. A potential cause of senile plaque accumulation. J Biol Chem 270:18666–18671. Hardingham TE, Fosang AJ (1992) Proteoglycans: many forms and many functions. FASEB J 6:861–870. Hartig W, Brauer K, Bigl V, Bruckner G (1994) Chondroitin sulfate proteoglycan-immunoreactivity of lectin-labeled perineuronal nets around parvalbumin-containing neurons. Brain Res 635:307–311. Hartig W, Derouiche A, Welt K, Brauer K, Grosche J, Mader M, Reichenbach A, Bruckner G (1999) Cortical neurons immunoreactive for the potassium channel Kv3.1b subunit are predominantly surrounded by perineuronal nets presumed as a buffering system for cations. Brain Res 842:15–29. Hartig W, Klein C, Brauer K, Schuppel KF, Arendt T, Bigl V, Bruckner G (2001) Hyperphosphorylated protein tau is restricted to neurons devoid of perineuronal nets in the cortex of aged bison. Neurobiol Aging 22:25–33. Hensch TK (2005) Critical period plasticity in local cortical circuits. Nat Rev Neurosci 6:877–888. Hensch TK, Fagiolini M, Mataga N, Stryker MP, Baekkeskov S, Kash SF (1998) Local GABA circuit control of experience-dependent plasticity in developing visual cortex. Science 282:1504–1508. Hill JJ, Jin K, Mao XO, Xie L, Greenberg DA (2012) Intracerebral chondroitinase ABC and heparan sulfate proteoglycan glypican improve outcome from chronic stroke in rats. Proc Natl Acad Sci USA 109:9155–9160. Hobohm C, Gunther A, Grosche J, Rossner S, Schneider D, Bruckner G (2005a) Decomposition and long-lasting downregulation of extracellular matrix in perineuronal nets induced by focal cerebral ischemia in rats. J Neurosci Res 80:539–548. Hobohm C, Gunther A, Grosche J, Rossner S, Schneider D, Bruckner G (2005b) Decomposition and long-lasting downregulation of extracellular matrix in perineuronal nets induced by focal cerebral ischemia in rats. J Neurosci Res 80:539–548. Hobohm C, Hartig W, Brauer K, Bruckner G (1998) Low expression of extracellular matrix components in rat brain stem regions containing modulatory aminergic neurons. J Chem Neuroanat 15:135–142. Hoffmann K, Sivukhina E, Potschka H, Schachner M, Löscher W, Dityatev A (2009) Retarded kindling progression in mice deficient in the extracellular matrix glycoprotein tenascin-R. Epilepsia 50:859–869. Hsueh YP, Sheng M (1999) Regulated expression and subcellular localization of syndecan heparan sulfate proteoglycans and the syndecan-binding protein CASK/LIN-2 during rat brain development. J Neurosci 19:7415–7425. Huang WC, Kuo WC, Cherng JH, Hsu SH, Chen PR, Huang SH, Huang MC, Liu JC, Cheng H (2006) Chondroitinase ABC promotes axonal re-growth and behavior recovery in spinal cord injury. Biochem Biophys Res Commun 349:963–968. Hubel DH, Wiesel TN, LeVay S (1976) Functional architecture of area 17 in normal and monocularly deprived macaque monkeys. Cold Spring Harb Symp Quant Biol 40:581–589. Hunanyan AS, Garcia-Alias G, Alessi V, Levine JM, Fawcett JW, Mendell LM, Arvanian VL (2010) Role of chondroitin sulfate proteoglycans in axonal conduction in Mammalian spinal cord. J Neurosci 30:7761–7769. 210 S. Soleman et al. / Neuroscience 253 (2013) 194–213 Huntley GW (2012) Synaptic circuit remodelling by matrix metalloproteinases in health and disease. Nat Rev Neurosci 13:743–757. Hyatt AJ, Wang D, Kwok JC, Fawcett JW, Martin KR (2010) Controlled release of chondroitinase ABC from fibrin gel reduces the level of inhibitory glycosaminoglycan chains in lesioned spinal cord. J Control Release 147:24–29. Iqbal K, Alonso Adel C, Chen S, Chohan MO, El-Akkad E, Gong CX, Khatoon S, Li B, Liu F, Rahman A, Tanimukai H, Grundke-Iqbal I (2005) Tau pathology in Alzheimer disease and other tauopathies. Biochim Biophys Acta 1739:198–210. Irani SR, Alexander S, Waters P, Kleopa KA, Pettingill P, Zuliani L, Peles E, Buckley C, Lang B, Vincent A (2010) Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan’s syndrome and acquired neuromyotonia. Brain 133:2734–2748. Iseda T, Okuda T, Kane-Goldsmith N, Mathew M, Ahmed S, Chang YW, Young W, Grumet M (2008) Single, high-dose intraspinal injection of chondroitinase reduces glycosaminoglycans in injured spinal cord and promotes corticospinal axonal regrowth after hemisection but not contusion. J Neurotrauma 25:334–349. Ito S, Kimura K, Haneda M, Ishida Y, Sawada M, Isobe K (2007) Induction of matrix metalloproteinases (MMP3, MMP12 and MMP13) expression in the microglia by amyloid-beta stimulation via the PI3K/Akt pathway. Exp Gerontol 42:532–537. Ito S, Sawada M, Haneda M, Fujii S, Oh-Hashi K, Kiuchi K, Takahashi M, Isobe K (2005) Amyloid-beta peptides induce cell proliferation and macrophage colony-stimulating factor expression via the PI3kinase/Akt pathway in cultured Ra2 microglial cells. FEBS Lett 579:1995–2000. Jones LL, Margolis RU, Tuszynski MH (2003) The chondroitin sulfate proteoglycans neurocan, brevican, phosphacan, and versican are differentially regulated following spinal cord injury. Exp Neurol 182:399–411. Kalb RG, Hockfield S (1994) Electrical activity in the neuromuscular unit can influence the molecular development of motor neurons. Dev Biol 162:539–548. Kanekiyo T, Zhang J, Liu Q, Liu CC, Zhang L, Bu G (2011) Heparan sulphate proteoglycan and the low-density lipoprotein receptorrelated protein 1 constitute major pathways for neuronal amyloidbeta uptake. J Neurosci 31:1644–1651. Kantor DB, Chivatakarn O, Peer KL, Oster SF, Inatani M, Hansen MJ, Flanagan JG, Yamaguchi Y, Sretavan DW, Giger RJ, Kolodkin AL (2004) Semaphorin 5A is a bifunctional axon guidance cue regulated by heparan and chondroitin sulfate proteoglycans. Neuron 44:961–975. Karetko-Sysa M, Skangiel-Kramska J, Nowicka D (2011) Disturbance of perineuronal nets in the perilesional area after photothrombosis is not associated with neuronal death. Exp Neurol 231:113–126. Karimi-Abdolrezaee S, Schut D, Wang J, Fehlings MG (2012) Chondroitinase and growth factors enhance activation and oligodendrocyte differentiation of endogenous neural precursor cells after spinal cord injury. PLoS One 7:e37589. Katsman D, Zheng J, Spinelli K, Carmichael ST (2003) Tissue microenvironments within functional cortical subdivisions adjacent to focal stroke. J Cereb Blood Flow Metab 23:997–1009. Kim GW, Kim HJ, Cho KJ, Kim HW, Cho YJ, Lee BI (2009) The role of MMP-9 in integrin-mediated hippocampal cell death after pilocarpine-induced status epilepticus. Neurobiol Dis 36:169–180. Kobayashi K, Emson PC, Mountjoy CQ (1989) Vicia villosa lectinpositive neurones in human cerebral cortex. Loss in Alzheimertype dementia. Brain Res 498:170–174. Komitova M, Perfilieva E, Mattsson B, Eriksson PS, Johansson BB (2006) Enriched environment after focal cortical ischemia enhances the generation of astroglia and NG2 positive polydendrocytes in adult rat neocortex. Exp Neurol 199:113–121. Koppe G, Bruckner G, Brauer K, Hartig W, Bigl V (1997a) Developmental patterns of proteoglycan-containing extracellular matrix in perineuronal nets and neuropil of the postnatal rat brain. Cell Tissue Res 288:33–41. Koppe G, Bruckner G, Hartig W, Delpech B, Bigl V (1997b) Characterization of proteoglycan-containing perineuronal nets by enzymatic treatments of rat brain sections. Histochem J 29:11–20. Ksiazek I, Burkhardt C, Lin S, Seddik R, Maj M, Bezakova G, Jucker M, Arber S, Caroni P, Sanes JR, Bettler B, Ruegg MA (2007) Synapse loss in cortex of agrin-deficient mice after genetic rescue of perinatal death. J Neurosci 27:7183–7195. Kuperstein I, Broersen K, Benilova I, Rozenski J, Jonckheere W, Debulpaep M, Vandersteen A, Segers-Nolten I, Van Der Werf K, Subramaniam V, Braeken D, Callewaert G, Bartic C, D’Hooge R, Martins IC, Rousseau F, Schymkowitz J, De Strooper B (2010) Neurotoxicity of Alzheimer’s disease Abeta peptides is induced by small changes in the Abeta42 to Abeta40 ratio. EMBO J 29:3408–3420. Kurihara D, Yamashita T (2012) Chondroitin sulfate proteoglycans down-regulate spine formation in cortical neurons by targeting tropomyosin-related kinase B (TrkB) protein. J Biol Chem 287:13822–13828. Kwok JC, Afshari F, Garcia-Alias G, Fawcett JW (2008) Proteoglycans in the central nervous system: plasticity, regeneration and their stimulation with chondroitinase ABC. Restor Neurol Neurosci 26:131–145. Kwok JC, Dick G, Wang D, Fawcett JW (2011) Extracellular matrix and perineuronal nets in CNS repair. Dev Neurobiol 71:1073–1089. Lacor PN, Buniel MC, Furlow PW, Clemente AS, Velasco PT, Wood M, Viola KL, Klein WL (2007) Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer’s disease. J Neurosci 27:796–807. Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, Morgan TE, Rozovsky I, Trommer B, Viola KL, Wals P, Zhang C, Finch CE, Krafft GA, Klein WL (1998) Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci USA 95:6448–6453. Lauren J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM (2009) Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature 457:1128–1132. Lee H, McKeon RJ, Bellamkonda RV (2010) Sustained delivery of thermostabilized chABC enhances axonal sprouting and functional recovery after spinal cord injury. Proc Natl Acad Sci USA 107:3340–3345. Lemons ML, Howland DR, Anderson DK (1999) Chondroitin sulfate proteoglycan immunoreactivity increases following spinal cord injury and transplantation. Exp Neurol 160:51–65. Leuba G, Kraftsik R, Saini K (1998) Quantitative distribution of parvalbumin, calretinin, and calbindin D-28k immunoreactive neurons in the visual cortex of normal and Alzheimer cases. Exp Neurol 152:278–291. Li R, Polat U, Makous W, Bavelier D (2009) Enhancing the contrast sensitivity function through action video game training. Nat Neurosci 12:549–551. Li W, Poteet E, Xie L, Liu R, Wen Y, Yang SH (2011) Regulation of matrix metalloproteinase 2 by oligomeric amyloid beta protein. Brain Res 1387:141–148. Litwack ED, Ivins JK, Kumbasar A, Paine-Saunders S, Stipp CS, Lander AD (1998) Expression of the heparan sulfate proteoglycan glypican-1 in the developing rodent. Dev Dyn 211:72–87. Liu T, Xu J, Chan BP, Chew SY (2012) Sustained release of neurotrophin-3 and chondroitinase ABC from electrospun collagen nanofiber scaffold for spinal cord injury repair. J Biomed Mater Res A 100:236–242. Lo FS, Zhao S, Erzurumlu RS (2011) Astrocytes promote peripheral nerve injury-induced reactive synaptogenesis in the neonatal CNS. J Neurophysiol 106:2876–2887. Lukasiuk K, Wilczynski GM, Kaczmarek L (2011) Extracellular proteases in epilepsy. Epilepsy Res 96:191–206. Martin-de-Saavedra MD, del Barrio L, Canas N, Egea J, Lorrio S, Montell E, Verges J, Garcia AG, Lopez MG (2011) Chondroitin sulfate reduces cell death of rat hippocampal slices subjected to S. Soleman et al. / Neuroscience 253 (2013) 194–213 oxygen and glucose deprivation by inhibiting p38, NFkappaB and iNOS. Neurochem Int 58:676–683. Massey JM, Amps J, Viapiano MS, Matthews RT, Wagoner MR, Whitaker CM, Alilain W, Yonkof AL, Khalyfa A, Cooper NG, Silver J, Onifer SM (2008) Increased chondroitin sulfate proteoglycan expression in denervated brainstem targets following spinal cord injury creates a barrier to axonal regeneration overcome by chondroitinase ABC and neurotrophin-3. Exp Neurol 209:426–445. Massey JM, Hubscher CH, Wagoner MR, Decker JA, Amps J, Silver J, Onifer SM (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. Matsui F, Oohira A (2004) Proteoglycans and injury of the central nervous system. Congenit Anom (Kyoto) 44:181–188. Matsumoto H, Kumon Y, Watanabe H, Ohnishi T, Shudou M, Chuai M, Imai Y, Takahashi H, Tanaka J (2008) Accumulation of macrophage-like cells expressing NG2 proteoglycan and Iba1 in ischemic core of rat brain after transient middle cerebral artery occlusion. J Cereb Blood Flow Metab 28:149–163. Matthews RT, Kelly GM, Zerillo CA, Gray G, Tiemeyer M, Hockfield S (2002) Aggrecan glycoforms contribute to the molecular heterogeneity of perineuronal nets. J Neurosci 22:7536–7547. McCroskery S, Bailey A, Lin L, Daniels MP (2009) Transmembrane agrin regulates dendritic filopodia and synapse formation in mature hippocampal neuron cultures. Neuroscience 163:168–179. McKeon RJ, Hoke A, Silver J (1995) Injury-induced proteoglycans inhibit the potential for laminin-mediated axon growth on astrocytic scars. Exp Neurol 136:32–43. McKeon RJ, Jurynec MJ, Buck CR (1999) The chondroitin sulfate proteoglycans neurocan and phosphacan are expressed by reactive astrocytes in the chronic CNS glial scar. J Neurosci 19:10778–10788. McRae PA, Baranov E, Rogers SL, Porter BE (2012) Persistent decrease in multiple components of the perineuronal net following status epilepticus. Eur J Neurosci 36:3471–3482. Meredith Jr JE, Fazeli B, Schwartz MA (1993) The extracellular matrix as a cell survival factor. Mol Biol Cell 4:953–961. Michaluk P, Mikasova L, Groc L, Frischknecht R, Choquet D, Kaczmarek L (2009) Matrix metalloproteinase-9 controls NMDA receptor surface diffusion through integrin beta1 signaling. J Neurosci 29:6007–6012. Michaluk P, Wawrzyniak M, Alot P, Szczot M, Wyrembek P, Mercik K, Medvedev N, Wilczek E, De Roo M, Zuschratter W, Muller D, Wilczynski GM, Mozrzymas JW, Stewart MG, Kaczmarek L, Wlodarczyk J (2011) Influence of matrix metalloproteinase MMP9 on dendritic spine morphology. J Cell Sci 124:3369–3380. Miyata S, Komatsu Y, Yoshimura Y, Taya C, Kitagawa H (2012) Persistent cortical plasticity by upregulation of chondroitin 6sulfation. Nat Neurosci 15:414–422. Miyata S, Nishimura Y, Nakashima T (2007) Perineuronal nets protect against amyloid beta-protein neurotoxicity in cultured cortical neurons. Brain Res 1150:200–206. Moon LD, Asher RA, Rhodes KE, Fawcett JW (2001) Regeneration of CNS axons back to their target following treatment of adult rat brain with chondroitinase ABC. Nat Neurosci 4:465–466. Morawski M, Bruckner G, Jager C, Seeger G, Arendt T (2010) Neurons associated with aggrecan-based perineuronal nets are protected against tau pathology in subcortical regions in Alzheimer’s disease. Neuroscience 169:1347–1363. Morawski M, Bruckner G, Jager C, Seeger G, Matthews RT, Arendt T (2012) Involvement of perineuronal and perisynaptic extracellular matrix in Alzheimer’s disease neuropathology. Brain Pathol 22:547–561. Morawski M, Bruckner MK, Riederer P, Bruckner G, Arendt T (2004) Perineuronal nets potentially protect against oxidative stress. Exp Neurol 188:309–315. Morellini F, Sivukhina E, Stoenica L, Oulianova E, Bukalo O, Jakovcevski I, Dityatev A, Irintchev A, Schachner M (2010) 211 Improved reversal learning and working memory and enhanced reactivity to novelty in mice with enhanced GABAergic innervation in the dentate gyrus. Cereb Cortex 20:2712–2727. Morris NP, Henderson Z (2000) Perineuronal nets ensheath fast spiking, parvalbumin-immunoreactive neurons in the medial septum/diagonal band complex. Eur J Neurosci 12:828–838. Mroczko B, Groblewska M, Barcikowska M (2013) The Role of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases in the Pathophysiology of Neurodegeneration: A Literature Study. J Alzheimers Dis 37:273–283. Nagy V, Bozdagi O, Matynia A, Balcerzyk M, Okulski P, Dzwonek J, Costa RM, Silva AJ, Kaczmarek L, Huntley GW (2006) Matrix metalloproteinase-9 is required for hippocampal late-phase longterm potentiation and memory. J Neurosci 26:1923–1934. Nakamae T, Tanaka N, Nakanishi K, Kamei N, Sasaki H, Hamasaki T, Yamada K, Yamamoto R, Mochizuki Y, Ochi M (2009) Chondroitinase ABC promotes corticospinal axon growth in organotypic cocultures. Spinal Cord 47:161–165. Nobile C, Michelucci R, Andreazza S, Pasini E, Tosatto SC, Striano P (2009) LGI1 mutations in autosomal dominant and sporadic lateral temporal epilepsy. Hum Mutat 30:530–536. Noguchi A, Matsumura S, Dezawa M, Tada M, Yanazawa M, Ito A, Akioka M, Kikuchi S, Sato M, Ideno S, Noda M, Fukunari A, Muramatsu S, Itokazu Y, Sato K, Takahashi H, Teplow DB, Nabeshima Y, Kakita A, Imahori K, Hoshi M (2009) Isolation and characterization of patient-derived, toxic, high mass amyloid betaprotein (Abeta) assembly from Alzheimer disease brains. J Biol Chem 284:32895–32905. Nothias F, Fishell G, Altaba A (1998) Cooperation of intrinsic and extrinsic signals in the elaboration of regional identity in the posterior cerebral cortex. Curr Biol 8:459–462. O’Callaghan P, Sandwall E, Li JP, Yu H, Ravid R, Guan ZZ, van Kuppevelt TH, Nilsson LN, Ingelsson M, Hyman BT, Kalimo H, Lindahl U, Lannfelt L, Zhang X (2008) Heparan sulfate accumulation with Abeta deposits in Alzheimer’s disease and Tg2576 mice is contributed by glial cells. Brain Pathol 18:548–561. Okamoto M, Mori S, Ichimura M, Endo H (1994) Chondroitin sulfate proteoglycans protect cultured rat’s cortical and hippocampal neurons from delayed cell death induced by excitatory amino acids. Neurosci Lett 172:51–54. Okulski P, Jay TM, Jaworski J, Duniec K, Dzwonek J, Konopacki FA, Wilczynski GM, Sanchez-Capelo A, Mallet J, Kaczmarek L (2007) TIMP-1 abolishes MMP-9-dependent long-lasting long-term potentiation in the prefrontal cortex. Biol Psychiatry 62:359–362. Orlando C, Ster J, Gerber U, Fawcett JW, Raineteau O (2012) Perisynaptic chondroitin sulfate proteoglycans restrict structural plasticity in an integrin-dependent manner. J Neurosci 32(18009– 18017):18017a. Owuor K, Harel NY, Englot DJ, Hisama F, Blumenfeld H, Strittmatter SM (2009) LGI1-associated epilepsy through altered ADAM23dependent neuronal morphology. Mol Cell Neurosci 42:448–457. Paradis S, Harrar DB, Lin Y, Koon AC, Hauser JL, Griffith EC, Zhu L, Brass LF, Chen C, Greenberg ME (2007) An RNAi-based approach identifies molecules required for glutamatergic and GABAergic synapse development. Neuron 53:217–232. Parameshwaran K, Sims C, Kanju P, Vaithianathan T, Shonesy BC, Dhanasekaran M, Bahr BA, Suppiramaniam V (2007) Amyloid beta-peptide Abeta(1–42) but not Abeta(1–40) attenuates synaptic AMPA receptor function. Synapse 61:367–374. Parodi J, Sepulveda FJ, Roa J, Opazo C, Inestrosa NC, Aguayo LG (2010) Beta-amyloid causes depletion of synaptic vesicles leading to neurotransmission failure. J Biol Chem 285:2506–2514. Pasterkamp RJ, De WF, Holtmaat AJ, Verhaagen J (1998) Evidence for a role of the chemorepellent semaphorin III and its receptor neuropilin-1 in the regeneration of primary olfactory axons. J Neurosci 18:9962–9976. Pasterkamp RJ, Giger RJ (2009) Semaphorin function in neural plasticity and disease. Curr Opin Neurobiol 19:263–274. Pasterkamp RJ, Giger RJ, Ruitenberg MJ, Holtmaat AJ, De WJ, De WF, Verhaagen J (1999) Expression of the gene encoding the 212 S. Soleman et al. / Neuroscience 253 (2013) 194–213 chemorepellent semaphorin III is induced in the fibroblast component of neural scar tissue formed following injuries of adult but not neonatal CNS. Mol Cell Neurosci 13:143–166. Pasterkamp RJ, Kolodkin AL (2003) Semaphorin junction: making tracks toward neural connectivity. Curr Opin Neurobiol 13:79–89. Perry G, Siedlak SL, Richey P, Kawai M, Cras P, Kalaria RN, Galloway PG, Scardina JM, Cordell B, Greenberg BD, et al (1991) Association of heparan sulfate proteoglycan with the neurofibrillary tangles of Alzheimer’s disease. J Neurosci 11:3679–3683. Pizzorusso T, Medini P, Berardi N, Chierzi S, Fawcett JW, Maffei L (2002) Reactivation of ocular dominance plasticity in the adult visual cortex. Science 298:1248–1251. Pizzorusso T, Medini P, Landi S, Baldini S, Berardi N, Maffei L (2006) Structural and functional recovery from early monocular deprivation in adult rats. Proc Natl Acad Sci USA 103:8517–8522. Pye DA, Vives RR, Turnbull JE, Hyde P, Gallagher JT (1998) Heparan sulfate oligosaccharides require 6-O-sulfation for promotion of basic fibroblast growth factor mitogenic activity. J Biol Chem 273:22936–22942. Pyka M, Wetzel C, Aguado A, Geissler M, Hatt H, Faissner A (2011) Chondroitin sulfate proteoglycans regulate astrocyte-dependent synaptogenesis and modulate synaptic activity in primary embryonic hippocampal neurons. Eur J Neurosci 33:2187–2202. Ramon y Cajal S (1928) Degeneration and regeneration of the nervous system. London: Oxford University Press. Rosenberg GA (2009) Matrix metalloproteinases and their multiple roles in neurodegenerative diseases. Lancet Neurol 8:205–216. Rothwell PM, Coull AJ, Silver LE, Fairhead JF, Giles MF, Lovelock CE, Redgrave JN, Bull LM, Welch SJ, Cuthbertson FC, Binney LE, Gutnikov SA, Anslow P, Banning AP, Mant D, Mehta Z (2005) Population-based study of event-rate, incidence, case fatality, and mortality for all acute vascular events in all arterial territories (Oxford Vascular Study). Lancet 366:1773–1783. Royer-Zemmour B, Ponsole-Lenfant M, Gara H, Roll P, Leveque C, Massacrier A, Ferracci G, Cillario J, Robaglia-Schlupp A, Vincentelli R, Cau P, Szepetowski P (2008) Epileptic and developmental disorders of the speech cortex: ligand/receptor interaction of wild-type and mutant SRPX2 with the plasminogen activator receptor uPAR. Hum Mol Genet 17:3617–3630. Sagane K, Hayakawa K, Kai J, Hirohashi T, Takahashi E, Miyamoto N, Ino M, Oki T, Yamazaki K, Nagasu T (2005) Ataxia and peripheral nerve hypomyelination in ADAM22-deficient mice. BMC Neurosci 6:33. Sahay A, Kim CH, Sepkuty JP, Cho E, Huganir RL, Ginty DD, Kolodkin AL (2005) Secreted semaphorins modulate synaptic transmission in the adult hippocampus. J Neurosci 25:3613–3620. Sale A, Maya Vetencourt JF, Medini P, Cenni MC, Baroncelli L, De PR, Maffei L (2007) Environmental enrichment in adulthood promotes amblyopia recovery through a reduction of intracortical inhibition. Nat Neurosci 10:679–681. Schulte U, Thumfart JO, Klocker N, Sailer CA, Bildl W, Biniossek M, Dehn D, Deller T, Eble S, Abbass K, Wangler T, Knaus HG, Fakler B (2006) The epilepsy-linked Lgi1 protein assembles into presynaptic Kv1 channels and inhibits inactivation by Kvbeta1. Neuron 49:697–706. Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA, Rowan MJ, Lemere CA, Regan CM, Walsh DM, Sabatini BL, Selkoe DJ (2008) Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 14:837–842. Shen Y, Tenney AP, Busch SA, Horn KP, Cuascut FX, Liu K, He Z, Silver J, Flanagan JG (2009) PTPsigma is a receptor for chondroitin sulfate proteoglycan, an inhibitor of neural regeneration. Science 326:592–596. Silingardi D, Angelucci A, De PR, Borsotti M, Squitieri G, Brambilla R, Putignano E, Pizzorusso T, Berardi N (2011) ERK pathway activation bidirectionally affects visual recognition memory and synaptic plasticity in the perirhinal cortex. Front Behav Neurosci 5:84. Smith-Thomas LC, Fok-Seang J, Stevens J, Du JS, Muir E, Faissner A, Geller HM, Rogers JH, Fawcett JW (1994) An inhibitor of neurite outgrowth produced by astrocytes. J Cell Sci 107(Pt 6):1687–1695. Smith-Thomas LC, Stevens J, Fok-Seang J, Faissner A, Rogers JH, Fawcett JW (1995) Increased axon regeneration in astrocytes grown in the presence of proteoglycan synthesis inhibitors. J Cell Sci 108(Pt 3):1307–1315. Snow AD, Kinsella MG, Parks E, Sekiguchi RT, Miller JD, Kimata K, Wight TN (1995) Differential binding of vascular cell-derived proteoglycans (perlecan, biglycan, decorin, and versican) to the beta-amyloid protein of Alzheimer’s disease. Arch Biochem Biophys 320:84–95. Snow AD, Mar H, Nochlin D, Kimata K, Kato M, Suzuki S, Hassell J, Wight TN (1988) The presence of heparan sulfate proteoglycans in the neuritic plaques and congophilic angiopathy in Alzheimer’s disease. Am J Pathol 133:456–463. Snow AD, Mar H, Nochlin D, Sekiguchi RT, Kimata K, Koike Y, Wight TN (1990a) Early accumulation of heparan sulfate in neurons and in the beta-amyloid protein-containing lesions of Alzheimer’s disease and Down’s syndrome. Am J Pathol 137:1253–1270. Snow AD, Sekiguchi R, Nochlin D, Fraser P, Kimata K, Mizutani A, Arai M, Schreier WA, Morgan DG (1994a) An important role of heparan sulfate proteoglycan (Perlecan) in a model system for the deposition and persistence of fibrillar A beta-amyloid in rat brain. Neuron 12:219–234. Snow AD, Sekiguchi RT, Nochlin D, Kalaria RN, Kimata K (1994b) Heparan sulfate proteoglycan in diffuse plaques of hippocampus but not of cerebellum in Alzheimer’s disease brain. Am J Pathol 144:337–347. Snow AD, Wight TN (1989) Proteoglycans in the pathogenesis of Alzheimer’s disease and other amyloidoses. Neurobiol Aging 10:481–497. Snow DM, Lemmon V, Carrino DA, Caplan AI, Silver J (1990b) Sulfated proteoglycans in astroglial barriers inhibit neurite outgrowth in vitro. Exp Neurol 109:111–130. Sofroniew MV (2009) Molecular dissection of reactive astrogliosis and glial scar formation. Trends Neurosci 32:638–647. Soleman S, Yip PK, Duricki DA, Moon LD (2012) Delayed treatment with chondroitinase ABC promotes sensorimotor recovery and plasticity after stroke in aged rats. Brain 135:1210–1223. Southwell DG, Froemke RC, Alvarez-Buylla A, Stryker MP, Gandhi SP (2010) Cortical plasticity induced by inhibitory neuron transplantation. Science 327:1145–1148. Spatazza J, Di LE, Joliot A, Dupont E, Moya KL, Prochiantz A (2013) Homeoprotein signaling in development, health, and disease: a shaking of dogmas offers challenges and promises from bench to bed. Pharmacol Rev 65:90–104. Spicer AP, Joo A, Bowling Jr RA (2003) A hyaluronan binding link protein gene family whose members are physically linked adjacent to chondroitin sulfate proteoglycan core protein genes: the missing links. J Biol Chem 278:21083–21091. Sugiyama S, Di Nardo AA, Aizawa S, Matsuo I, Volovitch M, Prochiantz A, Hensch TK (2008) Experience-dependent transfer of Otx2 homeoprotein into the visual cortex activates postnatal plasticity. Cell 134:508–520. Szklarczyk A, Lapinska J, Rylski M, McKay RD, Kaczmarek L (2002) Matrix metalloproteinase-9 undergoes expression and activation during dendritic remodeling in adult hippocampus. J Neurosci 22:920–930. Tester NJ, Howland DR (2008) Chondroitinase ABC improves basic and skilled locomotion in spinal cord injured cats. Exp Neurol 209:483–496. Tom VJ, Houle JD (2008) Intraspinal microinjection of chondroitinase ABC following injury promotes axonal regeneration out of a peripheral nerve graft bridge. Exp Neurol 211:315–319. Tozaki H, Matsumoto A, Kanno T, Nagai K, Nagata T, Yamamoto S, Nishizaki T (2002) The inhibitory and facilitatory actions of amyloid-beta peptides on nicotinic ACh receptors and AMPA receptors. Biochem Biophys Res Commun 294:42–45. S. Soleman et al. / Neuroscience 253 (2013) 194–213 Tran MD, Furones-Alonso O, Sanchez-Molano J, Bramlett HM (2012) Trauma-induced expression of astrocytic thrombospondin-1 is regulated by P2 receptors coupled to protein kinase cascades. Neuroreport 23:721–726. Tropea D, Caleo M, Maffei L (2003) Synergistic effects of brainderived neurotrophic factor and chondroitinase ABC on retinal fiber sprouting after denervation of the superior colliculus in adult rats. J Neurosci 23:7034–7044. van Horssen J, Kleinnijenhuis J, Maass CN, Rensink AA, Otte-Holler I, David G, van den Heuvel LP, Wesseling P, de Waal RM, Verbeek MM (2002a) Accumulation of heparan sulfate proteoglycans in cerebellar senile plaques. Neurobiol Aging 23:537–545. van Horssen J, Wilhelmus MM, Heljasvaara R, Pihlajaniemi T, Wesseling P, de Waal RM, Verbeek MM (2002b) Collagen XVIII: a novel heparan sulfate proteoglycan associated with vascular amyloid depositions and senile plaques in Alzheimer’s disease brains. Brain Pathol 12:456–462. Verbeek MM, Otte-Holler I, van den Born J, van den Heuvel LP, David G, Wesseling P, de Waal RM (1999) Agrin is a major heparan sulfate proteoglycan accumulating in Alzheimer’s disease brain. Am J Pathol 155:2115–2125. Verret L, Mann EO, Hang GB, Barth AM, Cobos I, Ho K, Devidze N, Masliah E, Kreitzer AC, Mody I, Mucke L, Palop JJ (2012) Inhibitory interneuron deficit links altered network activity and cognitive dysfunction in Alzheimer model. Cell 149:708–721. Villette V, Poindessous-Jazat F, Simon A, Lena C, Roullot E, Bellessort B, Epelbaum J, Dutar P, Stephan A (2010) Decreased rhythmic GABAergic septal activity and memoryassociated theta oscillations after hippocampal amyloid-beta pathology in the rat. J Neurosci 30:10991–11003. Vo T, Carulli D, Ehlert EM, Kwok JC, Dick G, Mecollari V, Moloney EB, Neufeld G, de Winter F, Fawcett JW, Verhaagen J (2013) The chemorepulsive axon guidance protein semaphorin3A is a constituent of perineuronal nets in the adult rodent brain. Mol Cell Neurosci 56C:186–200. Vorobyov V, Kwok JC, Fawcett JW, Sengpiel F (2013) Effects of digesting chondroitin sulfate proteoglycans on plasticity in cat primary visual cortex. J Neurosci 33:234–243. Wang D, Ichiyama RM, Zhao R, Andrews MR, Fawcett JW (2011) Chondroitinase combined with rehabilitation promotes recovery of forelimb function in rats with chronic spinal cord injury. J Neurosci 31:9332–9344. Ward NS (2005) Plasticity and the functional reorganization of the human brain. Int J Psychophysiol 58:158–161. Wenk GL (2003) Neuropathologic changes in Alzheimer’s disease. J Clin Psychiatry 64(Suppl. 9):7–10. 213 Wilczynski GM, Konopacki FA, Wilczek E, Lasiecka Z, Gorlewicz A, Michaluk P, Wawrzyniak M, Malinowska M, Okulski P, Kolodziej LR, Konopka W, Duniec K, Mioduszewska B, Nikolaev E, Walczak A, Owczarek D, Gorecki DC, Zuschratter W, Ottersen OP, Kaczmarek L (2008) Important role of matrix metalloproteinase 9 in epileptogenesis. J Cell Biol 180:1021–1035. Xu J, Xiao N, Xia J (2010) Thrombospondin 1 accelerates synaptogenesis in hippocampal neurons through neuroligin 1. Nat Neurosci 13:22–24. Yamagata T, Saito H, Habuchi O, Suzuki S (1968) Purification and properties of bacterial chondroitinases and chondrosulfatases. J Biol Chem 243:1523–1535. Yamaguchi Y (2000) Lecticans: organizers of the brain extracellular matrix. Cell Mol Life Sci 57:276–289. Yan P, Hu X, Song H, Yin K, Bateman RJ, Cirrito JR, Xiao Q, Hsu FF, Turk JW, Xu J, Hsu CY, Holtzman DM, Lee JM (2006) Matrix metalloproteinase-9 degrades amyloid-beta fibrils in vitro and compact plaques in situ. J Biol Chem 281:24566–24574. Yin KJ, Cirrito JR, Yan P, Hu X, Xiao Q, Pan X, Bateman R, Song H, Hsu FF, Turk J, Xu J, Hsu CY, Mills JC, Holtzman DM, Lee JM (2006) Matrix metalloproteinases expressed by astrocytes mediate extracellular amyloid-beta peptide catabolism. J Neurosci 26:10939–10948. Yoshiyama Y, Asahina M, Hattori T (2000) Selective distribution of matrix metalloproteinase-3 (MMP-3) in Alzheimer’s disease brain. Acta Neuropathol 99:91–95. Yuan W, Matthews RT, Sandy JD, Gottschall PE (2002) Association between protease-specific proteolytic cleavage of brevican and synaptic loss in the dentate gyrus of kainate-treated rats. Neuroscience 114:1091–1101. Zhang JW, Deb S, Gottschall PE (1998) Regional and differential expression of gelatinases in rat brain after systemic kainic acid or bicuculline administration. Eur J Neurosci 10:3358–3368. Zhao RR, Muir EM, Alves JN, Rickman H, Allan AY, Kwok JC, Roet KC, Verhaagen J, Schneider BL, Bensadoun JC, Ahmed SG, Yanez-Munoz RJ, Keynes RJ, Fawcett JW, Rogers JH (2011) Lentiviral vectors express chondroitinase ABC in cortical projections and promote sprouting of injured corticospinal axons. J Neurosci Methods 201:228–238. Zhou XH, Brakebusch C, Matthies H, Oohashi T, Hirsch E, Moser M, Krug M, Seidenbecher CI, Boeckers TM, Rauch U, Buettner R, Gundelfinger ED, Fassler R (2001) Neurocan is dispensable for brain development. Mol Cell Biol 21:5970–5978. Zimmermann DR, Dours-Zimmermann MT (2008) Extracellular matrix of the central nervous system: from neglect to challenge. Histochem Cell Biol 130:635–653. (Accepted 26 August 2013) (Available online 4 September 2013)