Targeting the neural extracellular matrix in neurological disorders

doi:10.1016/j.neuroscience.2013.08.050

Neuroscience

Volume 253, 3 December 2013, Pages 194-213

https://doi.org/10.1016/j.neuroscience.2013.08.050 Get rights and content

Highlights

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The enzymatic degradation of ECM stimulates developmental forms of plasticity.
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Weakening ECM aids functional recovery in regeneration, stroke, and amblyopia.
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ECM molecules shape epileptogenesis and might be new valuable therapeutic targets.
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Heparan sulfate proteoglycans regulate turnover of beta-amyloid.

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 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.

Section snippets

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

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 side-chains. 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

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

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

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,

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

Targeting the ECM and glial scar after spinal cord injury

After SCI, reactive astrocytes and OPCs greatly up-regulate 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

Targeting the ECM and glial scar after stroke

After ischemic stroke a number of growth-inhibitory molecules are differentially expressed within the peri-infarct 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 up-regulated 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,

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

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

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 Aβ peptides (amyloid plaques in brain parenchyma and amyloid deposits around blood

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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Citation Excerpt :
A previous study showed that neurocan, a component of CSPGs, is upregulated in the ECM of the distal spinal cord after CST in adult rats, but not in infant rats [11], suggesting that CST induces changes in CSPG expression in the PNNs depending on the timing of the transection. CSPGs contain core proteins and glycosaminoglycan side chains of chondroitin sulfate (CS-GAG) that are considered to contribute to neural plasticity and development [12–15]. There are 5 sulfation patterns in the repeating disaccharide unit of GAG, i.e., chondroitin sulfate (CS)-O, CS-A, CS-C, CS-D, and CS-E.
Hind limb locomotor activity spontaneously recovers after complete spinal transection (CST) in neonatal rats, but the mechanisms underlying the recovery are poorly understood. The perineuronal net (PNN) surrounding the neuronal cell bodies comprises an extracellular matrix that regulates neuronal plasticity during development. Here, we examined the expression of chondroitin sulfate (CS), a major component of the PNN, on motoneurons after CST in neonatal rats, and compared it with that in juvenile rats, in which hindlimb locomotor activity does not recover spontaneously.
The spinal cord was transected at the mid-thoracic level in neonatal (postnatal day 5 [P5] and P10) and juvenile (P15 and P20) rats. Two weeks after CST, the percentage of motoneurons surrounded by chondroitin sulfate C (CS-C) − positive structures was significantly lower in rats with CST at P10 than in intact rats, and tended to be higher in rats with CST at P15 than in intact rats. The percentage of motoneurons with CS-A − positive structures was significantly lower in rats with CST at P15 than in intact rats.
These findings suggest that CS-A and CS-C are differentially expressed in the PNNs in rats with CST. The decrease in CS-C − positive PNNs might facilitate the formation of new synaptic contacts to motoneurons, resulting in the recovery of the hindlimb locomotor activity in rats with CST during the neonatal period.
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Neuroscience Forefront ReviewTargeting the neural extracellular matrix in neurological disorders

Highlights

Abstract

Section snippets

The role of the extracellular matrix

Extracellular components and function

The role and importance of perineuronal nets in system plasticity

Role of semaphorins and Otx2 in developmental plasticity

Targeting the extracellular matrix in neurological disorders

Traumatic central nervous system injury

Targeting the ECM and glial scar after spinal cord injury

Targeting the ECM and glial scar after stroke

Amblyopia and disorders of the visual system

Extracellular matrix and epilepsy

Extracellular matrix and Alzheimer’s disease

Acknowledgments

Prog Brain Res

Neuron

Trends Neurosci

Brain Res Dev Brain Res

Neuroscience

Neuroscience

Exp Neurol

Brain Res Brain Res Rev

Trends Neurosci

Cell

Mol Cell Neurosci

Exp Neurol

Mol Cell Neurosci

Brain Res

J Biol Chem

Cell

Neuron

Brain Res Rev

Brain Res Bull

Brain Res Rev

Exp Neurol

J Mol Biol

Mol Cell Neurosci

Prog Brain Res

J Biol Chem

Brain Res

Brain Res

Neurobiol Aging

J Chem Neuroanat

Functional regeneration of respiratory pathways after spinal cord injury

Nature

Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors

Nature

Expression of matrix metalloproteinase-9 and urinary-type plasminogen activator in Alzheimer’s disease brain

Clin Neuropathol

Neurocan is upregulated in injured brain and in cytokine-treated astrocytes

J Neurosci

Versican is upregulated in CNS injury and is a product of oligodendrocyte lineage cells

J Neurosci

Matrix metalloproteinase-9 (MMP-9) is synthesized in neurons of the human hippocampus and is capable of degrading the amyloid-beta peptide (1–40)

J Neurosci

Accelerated glial reactivity to stroke in aged rats correlates with reduced functional recovery

J Cereb Blood Flow Metab

Loss of perineuronal net N-acetylgalactosamine in Alzheimer’s disease

Acta Neuropathol

Proteoglycans in the developing brain: new conceptual insights for old proteins

Physiol Rev

The toxic Abeta oligomer and Alzheimer’s disease: an emperor in need of clothes

Nat Neurosci

Otx2 binding to perineuronal nets persistently regulates plasticity in the mature visual cortex

J Neurosci

Enriched rehabilitative training promotes improved forelimb motor function and enhanced dendritic growth after focal ischemic injury

J Neurosci

AAV-mediated expression of neuropilin1-Fc, a secreted receptor that inactivates semaphorin3a, enhances ocular dominance plasticity in the adult rat visual cortex

Semaphorin3A regulates synaptic function of differentiated hippocampal neurons

Eur J Neurosci

Neurite outgrowth inhibitors associated with glial cells and glial cell lines

Neuroreport

Chondroitinase ABC promotes selective reactivation of somatosensory cortex in squirrel monkeys after a cervical dorsal column lesion

Proc Natl Acad Sci USA

Manipulating the glial scar: chondroitinase ABC as a therapy for spinal cord injury

Brain Res Bull

Chondroitinase ABC promotes functional recovery after spinal cord injury

Nature

Neuroscience Forefront Review
Targeting the neural extracellular matrix in neurological disorders