Extracellular Matrix in Neural Plasticity and Regeneration

Abstract

The extracellular matrix (ECM) is a fundamental component of biological tissues. The ECM in the central nervous system (CNS) is unique in both composition and function. Functions such as learning, memory, synaptogenesis, and plasticity are regulated by numerous ECM molecules. The neural ECM acts as a non-specific physical barrier that modulates neuronal plasticity and axon regeneration. There are two specialized types of ECM in the CNS, diffuse perisynaptic ECM and condensed ECM, which selectively surround the perikaryon and initial part of dendritic trees in subtypes of neurons, forming perineuronal nets. This review presents the current knowledge about the role of important neuronal ECM molecules in maintaining the basic functions of a neuron, including electrogenesis and the ability to form neural circuits. The review mainly focuses on the role of ECM components that participate in the control of key events such as cell survival, axonal growth, and synaptic remodeling. Particular attention is drawn to the numerous molecular partners of the main ECM components. These regulatory molecules are integrated into the cell membrane or disposed into the matrix itself in solid or soluble form. The interaction of the main matrix components with molecular partners seems essential in molecular mechanisms controlling neuronal functions. Special attention is paid to the chondroitin sulfate proteoglycan 4, type 1 transmembrane protein, neural-glial antigen 2 (NG2/CSPG4), whose cleaved extracellular domain is such a molecular partner that it not only acts directly on neural and vascular cells, but also exerts its influence indirectly by binding to resident ECM molecules.

Keywords: CSPGs; HAPLN proteins; Hyaluronan; NG2; Perineuronal nets; Perisynaptic matrix; Tenascins.

Fig. 1

Possible mechanisms underlying the involvement of a type 1 transmembrane protein NG2/CSPG4 in CNS axon regeneration. In the area of CNS damage, the number of NG2 cells expressing NG2/CSPG4 increases dramatically. The D2 subdomain of NG2/CSPG4 contains 15 repeats for CS-GAG binding, as well as binding sites for collagens IV and VI, α4β1 integrins, and growth factors (GFs). As a result of the action of sheddase ADAM10 (α-secretase), the ectodomain (sNG2) is cleaved (orange arrows) and exerts a distant effect on the targets. In the damaged area, not only a sharp increase in the number of NG2⁺-cells was noted, but an increase in the intensity of sNG2 separation was also observed. The latter is integrated into the ECM network through collagens interacting with the collagen binding site in the D2 subdomain. Due to the dramatic increase in the number of NG2⁺ cells in the area of damage, it seems important to consider the potential effect of sNG2 on the regeneration of neural circuits. D2 subdomain-linked CS-GAG together with CS-GAG chains in lectans interact with receptor protein tyrosine phosphatase sigma (RPTPσ) and Nogo receptor 1 (NgR1). These interactions activate the RhoA-ROCK-LIMK-cofilin pathways, leading to the disintegration of the actin complex of the cytoskeleton and termination of axon growth. NG2/CSPG4 and sNG2, which have collagen and integrin-binding sites and acting through the ECM—integrin axis, may have a supportive effect on axon growth. In addition, acting as a coreceptor for GFs such as platelet-derived growth factor (PDGF) and fibroblast growth factor 2 (FGF2), the D2 subdomain can have a more pronounced effect on the axon, mediated by activation of receptor tyrosine kinases (RTK) in the axolemma. Thus, NG2/CSPG4 has the potential to exert both a permissive and a stabilizing effect on axonal growth, which has been recorded for this molecule in numerous in vivo and in vitro studies. D2 subdomain-linked CS-GAG, in solidarity with other CS-GAG present in various forms in the ECM, in addition to the mediated actions of RPTPσ and NgR1, may influence axonal growth via other known pathways, such as through the RPTPζ and NCAM complex, as well as the inhibition of pathway attractive guidance cues associated with semaphorins 3A and 5A. In the vicinity of the damaged axons, NG2/CSPG4 is expressed not only by NG2 glia, but also by pericytes, in which sNG2 shedding is increased under the same pathological conditions. This part of the NG2/CSPG4 molecule stimulates endothelial cell proliferation and angiogenesis, thereby enhancing axonal growth