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
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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
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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.
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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.
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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.
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(Accepted 26 August 2013)
(Available online 4 September 2013)