Targeting the neural extracellular matrix in neurological disorders

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.

Keywords: AD; ADDLs; Alzheimer’s disease; BDNF; CSPGs; ChABC; ECM; GAG; HSPGs; LGI1; LRP1; LTD; LTP; MMP; OPCs; Otx2; PNNs; PV; SCI; SRPX2; Sushi-repeat Protein, X-linked 2; amyloid-derived diffusible ligands; brain-derived neurotrophic factor; chondroitin sulfate proteoglycans; chondroitinase ABC; epilepsy; extracellular matrix; glycosaminoglycan; heparan sulfate proteoglycans; leucine-rich, glioma-inactivated 1; lipoprotein receptor-related protein 1; long-term depression; long-term potentiation; mEPSCs; matrix metalloproteinase; miniature excitatory postsynaptic currents; oligodendrocyte precursor cells; orthodenticle homeobox protein 2; parvalbumin; perineuronal nets; plasticity; proteoglycans; spinal cord injury; uPA; urokinase-type plasminogen activator.