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

Biochim Biophys Acta Gen Subj. 2017 Oct;1861(10):2420-2434. doi: 10.1016/j.bbagen.2017.06.010. Epub 2017 Jun 15.


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.

Keywords: Axon regeneration; Chondroitin sulfate proteoglycan; Hyaluronan; Parvalbumin-expressing inhibitory neuron; Perineuronal net; Synaptic plasticity.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Brain / metabolism*
  • Brain / physiology
  • Brain / physiopathology
  • Brain Chemistry*
  • Brain Injuries / metabolism*
  • Brain Injuries / pathology
  • Brain Injuries / physiopathology
  • Brain Injuries / rehabilitation
  • Chondroitin Sulfates / chemistry
  • Chondroitin Sulfates / metabolism*
  • Extracellular Matrix / chemistry
  • Extracellular Matrix / metabolism*
  • Humans
  • Hyaluronic Acid / chemistry
  • Hyaluronic Acid / metabolism*
  • Nerve Net / physiology
  • Nerve Net / physiopathology
  • Nerve Regeneration / physiology
  • Neurogenesis / physiology
  • Neuronal Plasticity / physiology
  • Neurons / cytology
  • Neurons / physiology
  • Parvalbumins / genetics
  • Parvalbumins / metabolism
  • Synapses / physiology


  • Parvalbumins
  • Hyaluronic Acid
  • Chondroitin Sulfates