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  • Review Article
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Extracellular matrix molecules and synaptic plasticity

Nature Reviews Neuroscience volume 4, pages 456–468 (2003)Cite this article

Key Points

  • In animals, organized groups of cells are surrounded by an extracellular matrix (ECM) of collagens, proteoglycans and glycoproteins. These molecules not only interact with each other, but they also activate signal transduction pathways, which coordinate cell proliferation, migration and differentiation.

  • In addition to its roles in development and regeneration in the nervous system, the ECM is involved in physiological processes in the adult brain, such as synaptic plasticity. This review focuses on this lesser-known function of ECM molecules in the adult nervous system.

  • Synaptic plasticity is the phenomenon by which the efficacy of synaptic transmission varies in an activity-dependent manner. A transient increase in synaptic efficacy is called short-term potentiation, whereas the persistent enhancement or reduction of synaptic strength of stimulated synapses are known as long-term potentiation (LTP) or long-term depression (LTD), respectively.

  • Because of the complexity and diversity of synaptic plasticity mechanisms, it is not difficult to imagine that more than one ECM molecule would affect synapse formation and synaptic modifications in the adult. To identify the best candidates, this review proposes a series of criteria that need to be fulfilled to show that an ECM molecule is required for synaptic plasticity.

  • ECM molecules that have been implicated in synaptic plasticity include laminins, reelin, heparin-binding growth-associated molecule (HB-GAM), neuronal activity-regulated pentraxin (Narp), tenascin-R, tenascin-C, and the chondroitin sulphate proteoglycans brevican and neurocan.

  • All of the ECM molecules that have been studied so far promote LTP in the CA1 region of the hippocampus, except for HB-GAM, which inhibits it. Short-term potentiation was typically not affected after manipulation of ECM molecules, except for reelin, which increased short-term potentiation.

  • These findings raise the question of how the effects of ECM molecules on synaptic plasticity are linked to developmental events. The sprouting of neurites that is stimulated by some of these molecules could promote the formation of new synapses, but it is equally conceivable that the barrier functions of certain ECM molecules are required for stabilization of nascent contacts.

Abstract

Interactions between cells and the extracellular matrix (ECM) have long been accepted to have pivotal roles in neural development and regeneration. Recent data also support the involvement of several ECM molecules in synaptic plasticity. Here, we review the present knowledge of the underlying mechanisms. These include interactions with cell surface receptors for ECM molecules coupled to the cytoskeleton and tyrosine kinase activities, and interactions with ion channels or neurotransmitter receptors. We hypothesize that ECM molecules derived from neurons and glia might also shape synaptic plasticity through regulation of organelle trafficking, and by imposing diffusion constraints for neurotransmitters and trophic factors.

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Figure 1: Extracellular matrix (ECM) in the brain.
Figure 2: Reelin and regulation of long-term potentiation.
Figure 3: Narp and postsynaptic differentiation of glutamatergic synapses on interneurons.
Figure 4: Regulation of perisomatic inhibition in the CA1 region of the hippocampus by glycoprotein tenascin-R and its associated HNK-1 carbohydrate.
Figure 5: Hypothetical mechanisms by which extracellular matrix (ECM) molecules could regulate synaptic plasticity.

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Acknowledgements

We greatly appreciate helpful discussions with H. Beck, V. Bolshakov, G. Bruckner, P. Giese, M. Kneussel, D. Kullmann, A. Luthi and contributions from all members of our laboratory cited in the references. This work was supported by grants from the Deutsche Forschungsgemeinschaft.

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  1. Zentrum für Molekulare Neurobiologie, University of Hamburg, Martinistr. 52, Hamburg, 20246, Germany

    Alexander Dityatev & Melitta Schachner

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  1. Alexander Dityatev
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DATABASES

LocusLink

agrin

ApoER2

brevican

fibronectin

GluR1–3

HB-GAM

integrins

laminins

Narp

neurocan

phosphacan

Reln

Synd3

TN-C

TN-R

VLDLR

Glossary

PROTEOGLYCANS

The proteoglycans have a much higher ratio of polysaccharide to protein than do collagens, fibronectin, and glycoproteins in the extracellular matrix. The polysaccharide chains in proteoglycans are long repeating linear polymers of specific disaccharides called glycosaminoglycans. Usually one sugar is a uronic acid and the other is either N-acetylglucosamine or N-acetylgalactosamine.

SPINES

Specialized regions of the dendrite that receive synaptic inputs from other neurons.

ACTIVE ZONE

A portion of the presynaptic membrane that faces the postsynaptic density across the synaptic cleft. It constitutes the site of synaptic vesicle clustering, docking and transmitter release.

METABOTROPIC

A term that describes a receptor that is associated with G proteins and exerts its effects through enzyme activation.

SCHAFFER COLLATERALS

Axons of the CA3 pyramidal cells of the hippocampus that form synapses with the apical dendrites of CA1 neurons.

CHONDROITIN SULPHATE PROTEOGLYCANS

Important components of the extracellular matrix and connective tissue. These proteins contain hydrophilic, negatively charged polymers of glucuronic acid and sulphated N-acetyl glucosamine residues.

CONTEXTUAL FEAR CONDITIONING

Hippocampus-dependent learning task in which animals associate a specific location and its surroundings with an electric shock.

ELEVATED PLUS-MAZE

In this experiment, animals are placed in the centre of an elevated four arm plus-like maze, in which two arms are closed and two arms are open. So, the animal can fall down from the open arms. Avoidance of being in open arms is taken as a measure of fearful behaviour.

IMMEDIATE EARLY GENES

Genes that are induced rapidly and transiently. Many immediate-early genes, such as fos, control the transcription of other genes, and thereby regulate expression of sets of proteins.

DOMINANT-NEGATIVE

A mutant molecule that binds to an interaction partner of the normal molecule and thereby blocks the functional complex.

STEP-DOWN PASSIVE AVOIDANCE TASK

A behavioural experiment, in which an animal learns to associate stepping down from a raised platform with an aversive stimulus, such as electric shock. The name of the task derives from the fact that the animal learns to passively stay at the platform to avoid the stimulus.

WATER-MAZE TASK

A learning task in which an animal is placed in a pool filled with opaque water and has to learn to escape to a hidden platform that is placed at a constant position. The animal must learn to use distal cues, and the spatial relationship between them and the platform.

PATCH CLAMP

Technique whereby a small electrode tip is sealed onto a patch of cell membrane, making it possible to record the flow of current through individual ion channels or pores within the patch. Disruption of the patch membrane provides the possibility to record currents from the whole cell.

G-PROTEIN-COUPLED INWARDLY RECTIFYING K+ CHANNELS

K+ channels that are regulated by neurotransmitters and hormones through G-protein-coupled receptors. They are called inward rectifiers because current flows through them more easily into than out of cells.

PEPTIDOMIMETICS

Peptides mimicking other molecules — for instance carbohydrates — in their ability to bind other molecules.

OCULAR DOMINANCE

In the mature primary visual cortex of mammals, most neurons respond predominantly to visual inputs from one eye or the other. This phenomenon is called ocular dominance. Cells that respond to a given eye are arranged in stripes — the ocular dominance columns — that alternate with stripes of neurons that respond to the other eye.

SYNAPTOSOMES

A preparation of presynaptic terminals and postsynaptic membranes, isolated after subcellular fractionation. These structures can take up, store and release neurotransmitters and could contain postsynaptic densities.

MOSSY FIBRES

Axons of dentate gyrus granule cells, which constitute the main excitatory input to CA3 pyramidal cells in the hippocampus.

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Dityatev, A., Schachner, M. Extracellular matrix molecules and synaptic plasticity. Nat Rev Neurosci 4, 456–468 (2003). https://doi.org/10.1038/nrn1115

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