Review
Formation and remodeling of the brain extracellular matrix in neural plasticity: Roles of chondroitin sulfate and hyaluronan

https://doi.org/10.1016/j.bbagen.2017.06.010Get rights and content

Highlights

  • The extracellular matrix (ECM) of the brain plays key roles in neural plasticity.

  • The brain ECM is rich in chondroitin sulfate and hyaluronan.

  • Several factors influence formation and remodeling of the brain ECM.

  • Perineuronal nets modulate maturation of parvalbumin-expressing inhibitory neurons.

  • Perisynaptic ECM controls synapse formation and dendritic spine dynamics.

Abstract

Background

The extracellular matrix (ECM) of the brain is rich in glycosaminoglycans such as chondroitin sulfate (CS) and hyaluronan. These glycosaminoglycans are organized into either diffuse or condensed ECM. Diffuse ECM is distributed throughout the brain and fills perisynaptic spaces, whereas condensed ECM selectively surrounds parvalbumin-expressing inhibitory neurons (PV cells) in mesh-like structures called perineuronal nets (PNNs). The brain ECM acts as a non-specific physical barrier that modulates neural plasticity and axon regeneration.

Scope of review

Here, we review recent progress in understanding of the molecular basis of organization and remodeling of the brain ECM, and the involvement of several types of experience-dependent neural plasticity, with a particular focus on the mechanism that regulates PV cell function through specific interactions between CS chains and their binding partners. We also discuss how the barrier function of the brain ECM restricts dendritic spine dynamics and limits axon regeneration after injury.

Major conclusions

The brain ECM not only forms physical barriers that modulate neural plasticity and axon regeneration, but also forms molecular brakes that actively controls maturation of PV cells and synapse plasticity in which sulfation patterns of CS chains play a key role. Structural remodeling of the brain ECM modulates neural function during development and pathogenesis.

General significance

Genetic or enzymatic manipulation of the brain ECM may restore neural plasticity and enhance recovery from nerve injury.

This article is part of a Special Issue entitled Neuro-glycoscience, edited by Kenji Kadomatsu and Hiroshi Kitagawa.

Introduction

Extracellular matrix (ECM) molecules in the brain fill the extracellular space, which occupies up to 20% of the adult brain volume, and play important roles in neuronal development, plasticity, and pathophysiology [1], [2]. The brain ECM is characterized by an abundance of long linear polysaccharides called glycosaminoglycans and the absence of fibrillar collagenous components. The brain ECM exists in either a diffuse or condensed form. A prominent example of condensed ECM is perineuronal nets (PNNs), which show lattice-like structures around subpopulations of neurons. On the other hand, diffuse ECM is found throughout the neuropil and fills perisynaptic spaces. Both types of ECM act as molecular brakes that restrict neural plasticity in the mature brain, because neural plasticity can be restored by enzymatic disruption or genetic manipulation of the brain ECM. In addition, the ECM is a key component of the major barrier to axon regeneration after injury in the central nervous system (CNS). Glycosaminoglycans in the brain ECM have been classically considered non-specific physical barriers of neural plasticity and regeneration. However, recent studies have proposed that ECM molecules actively regulate neuronal function through specific interactions with their binding partners. Here, we review recent progress in our understanding of the mechanisms of regulation of neural plasticity by the brain ECM, especially focusing on the structure-function relationship of the ECM molecules.

Section snippets

Structure and biosynthesis of glycosaminoglycans

Glycosaminoglycans are polysaccharides that consist of repeating disaccharide units; each unit comprises alternating hexosamine and hexuronic acid residues. Depending on the composition and glycosidic linkage of the disaccharide units, each glycosaminoglycan chain can be classified into one of four classes: chondroitin sulfate (CS), heparan sulfate (HS), keratan sulfate (KS) or hyaluronan. In the disaccharide units of KS, galactose replaces the hexuronic acid. The disaccharide units of CS, HS,

Molecular composition and structure of PNNs

PNNs are reticular structures that cover cell bodies and the proximal part of neurites of several neuronal populations. Since the discovery of PNNs by Camillo Golgi in 1882, researchers have described their detailed morphology and distribution in the CNS of many species [68]. Their function in the CNS was not clearly understood until the late 1990s, and recent studies have unveiled critical roles for PNNs in neural plasticity. At the molecular level, two classes of glycosaminoglycan chains, CS

PNNs act as molecular brakes to limit experience-dependent plasticity

Neural plasticity is the ability of neural circuits to reorganize in response to environmental stimuli and sensory experiences. Across brain regions, plasticity is most robust during a limited time window early in life, the so-called critical period [114], [115]. For example, in the visual cortex, imbalanced visual input during this period (age 5–8 years in humans) due to occlusion of one eye with a patch leads to a reduced response in the closed eye and subsequent persistent loss of visual

Extrinsic and intrinsic factors affecting PNN formation

Several factors influence the formation of PNNs during postnatal development. Sensory experience is one such factor. Sensory deprivation by dark rearing or whisker trimming attenuates the formation of PNNs in the visual cortex or somatosensory cortex, respectively [119], [157]. Notably, the expression level of Hapln1/Crtl1 is down-regulated by dark rearing and recovers following subsequent light exposure [79]. Hapln1/Crtl1-deficient adult mice show attenuated PNN formation and retain juvenile

CSPGs and hyaluronan in diffuse ECM

CSPGs and hyaluronan exist as two forms in the adult CNS: diffuse ECM and highly condensed ECM. The former is distributed throughout the neuropil and fills perisynaptic spaces, whereas the latter includes PNNs and the concentrated ECM at the nodes of Ranvier of myelinated axons. These ECM subtypes can be biochemically separated by sequential extraction: diffuse ECM is extracted with saline or mild detergent solution, whereas condensed ECM is only extracted by strong denaturants such as 6 M urea

CS chains and their receptors in the injured CNS

As described above, CSPGs act as either functional brakes or structural barriers that limit neural plasticity by regulating PV cell function or by preventing remodeling of dendritic spines, respectively. Inhibitory effects of CSPGs on neuronal function can also be observed when the CNS is injured. The injured adult mammalian CNS has very limited regenerative ability. Damage to the CNS induces formation of a glial scar, which consists predominately of reactive astrocytes and serves as a barrier

Conclusion

Brain ECM molecules, especially CSPGs and hyaluronan, act as non-specific physical barriers for neural plasticity and axon regeneration. Recent progress has also revealed that the ECM actively regulates neural plasticity. PNNs are ternary complexes of CSPGs, hyaluronan, and tenascin-R, and play important roles in several types of experience-dependent plasticity and learning and memory in various brain regions. Mechanistically, PNNs modify maturation of PV cells through specific interactions

Funding

This work was supported by the Lotte Shigemitsu Prize (to S.M.), and by Grants-in-Aid for Young Scientists (B) #15K21067 (to S.M.), for Scientific Research (B) #16H05088 (to H.K.), and for Scientific Research on Innovative Area #23110003 (to H.K.), and the Supported Program for the Strategic Research Foundation at Private Universities #S1201040 (to H.K.) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

Conflict of interest

None declared.

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