The roles of perineuronal nets and the perinodal extracellular matrix in neuronal function

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Perineuronal nets (PNNs) are extracellular matrix (ECM) chondroitin sulfate proteoglycan (CSPG)-containing structures that surround the soma and dendrites of various mammalian neuronal cell types. PNNs appear during development around the time that the critical periods for developmental plasticity end and are important for both their onset and closure. A similar structure — the perinodal ECM — surrounds the axonal nodes of Ranvier and appears as myelination is completed, acting as an ion-diffusion barrier that affects axonal conduction speed. Recent work has revealed the importance of PNNs in controlling plasticity in the CNS. Digestion, blocking or removal of PNNs influences functional recovery after a variety of CNS lesions. PNNs have further been shown to be involved in the regulation of memory and have been implicated in a number of psychiatric disorders.

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Fig. 1: Location and appearance of perineuronal nets.
Fig. 2: The structure of the perinodal extracellular matrix.
Fig. 3: A model for the role of perineuronal nets in memory.


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The authors’ work is supported by the UK Medical Research Council; the Christopher and Dana Reeve Foundation; the International Foundation for Research in Paraplegia; the EU European Research Area Networks (ERA-NET) AxonRepair project; the European Research Council; the Czech Centre of Reconstructive Neuroscience; the Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT; grant number 26110713); and the Mizutani Foundation for Glycoscience.

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Nature Reviews Neuroscience thanks H. Kitagawa and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Correspondence to James W. Fawcett.

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Extracellular matrix

(ECM). A diffuse extracellular matrix that surrounds the cells of the brain and is specialized around some neurons into a much more compacted structure, the perineuronal nets.

Nodes of Ranvier

The gaps between myelinating glia at which the naked axonal membrane fires action potentials.

Chondroitin sulfate proteoglycan

(CSPG). A molecule that consists of a protein core with a varying number of chondroitin sulfate chains attached through a covalent link to serine.


(GAG). One of the repeating disaccharides that form the carbohydrate chains of heparin sulfate and chondroitin sulfate proteoglycans and hyaluronan.

Critical periods

Periods of enhanced plasticity at the end of neural development during which the final pattern of CNS connectivity is refined. They are followed by critical period closure when plasticity declines to the adult level.


The addition of a sulfo group to a molecule. Chondroitin sulfate glycosaminoglycan chains are sulfated at the 4, 6, 2–6 and 4–6 positions. Sulfation motifs can give charge structures that define specific binding sites.

Ocular dominance plasticity

A phenomenon in which, when one mammalian eye is disadvantaged during the critical period by eye closure or an equivalent intervention, the projections from that eye in the brain lose in the competition for space to projections from the other eye, which leads to increased innervation from the non-deprived eye.

Long-term potentiation

(LTP). An increase in the postsynaptic potential caused by an input that occurs when this and another input to the same neuron are active simultaneously.

Long-term depression

(LTD). A decline in the postsynaptic potential caused by an input following prolonged stimulation.

Oxidative stress

Active metabolic events that can lead to the release of various free radicals and other oxidant molecules, usually from mitochondria.

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Fawcett, J.W., Oohashi, T. & Pizzorusso, T. The roles of perineuronal nets and the perinodal extracellular matrix in neuronal function. Nat Rev Neurosci 20, 451–465 (2019) doi:10.1038/s41583-019-0196-3

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