Review Article | Published:

The dual role of the extracellular matrix in synaptic plasticity and homeostasis

Nature Reviews Neuroscience volume 11, pages 735746 (2010) | Download Citation

Abstract

Recent studies have deepened our understanding of multiple mechanisms by which extracellular matrix (ECM) molecules regulate various aspects of synaptic plasticity and have strengthened a link between the ECM and learning and memory. New findings also support the view that the ECM is important for homeostatic processes, such as scaling of synaptic responses, metaplasticity and stabilization of synaptic connectivity. Activity-dependent modification of the ECM affects the formation of dendritic filopodia and the growth of dendritic spines. Thus, the ECM has a dual role as a promoter of structural and functional plasticity and as a degradable stabilizer of neural microcircuits. Both of these aspects are likely to be important for mental health.

Key points

  • Several extracellular matrix (ECM) components, such as Reelin, integrin ligands, tenascin C and hyaluronic acid, regulate induction of synaptic plasticity through their modulatory effects on NMDA (N-methyl-D-aspartate) receptors and L-type voltage-dependent Ca2+ channels, which are the major players in triggering activity-dependent synaptic changes.

  • Following induction of long-term potentiation (LTP), stabilization of new synaptic configurations requires integrin signalling through the Src family of tyrosine kinases, which contributes to the regulation of the localization and activity of small GTPases that coordinate actin cytoskeleton remodelling and stabilization.

  • β3 integrins and neuronal pentraxins regulate homeostatic scaling of excitatory postsynaptic currents on excitatory and inhibitory neurons, respectively, through control of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor trafficking and aggregation. Tenascin R is important for metaplastic adjustment of the threshold for induction of LTP in area CA1 of the hippocampus, where it regulates perisomatic innervation of pyramidal neurons.

  • Stabilization of functional microcircuits at the end of the 'critical period' in brain development is thought to involve formation of the chondroitin sulphate-rich ECM that serves as an inhibitory 'barrier' to restrain structural plasticity in the visual cortex and enable formation of erasure-resistant emotional memories in the amygdala.

  • Activity-dependent proteolytic cleavage of ECM components regulates various forms of synaptic plasticity. Proteolytic activity of matrix metalloproteinase 9 promotes hippocampal LTP through the activation of integrin-dependent signalling. Integrin activation is mediated by proteolytic unmasking of a cryptic Arg-Gly-Asp motif of a not yet identified ECM component.

  • The proteolytic function of the synaptic serine protease neurotrypsin is activated in an NMDA receptor-dependent manner when a presynaptic and a postsynaptic neuron fire together. Cleavage of agrin by neurotrypsin unmasks a previously unaccessible filopodia-promoting site on the released carboxy-terminal 22-kDa fragment (agrin 22). Activity-dependent generation of dendritic filopodia by released agrin 22 is thought to contribute to activity-dependent synaptogenesis and reorganization of neural circuits.

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Acknowledgements

We thank C. Sonderegger and L. Wanner for help with artwork. We gratefully acknowledge support by the Italian Institute of Technology (A.D.), the Deutsche Forschungsgemeinschaft (A.D. and M.S.), the New Jersey Commission for Spinal Cord Research and Stem Cell Research (M.S.), the Bundesministerium für Bildung und Forschung (M.S.) and the Swiss National Science Foundation (P.S.).

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Affiliations

  1. Department of Neuroscience and Brain Technologies, Italian Institute of Technology, via Morego 30, Genova, 16163 Italy.

    • Alexander Dityatev
  2. Zentrum fuer Molekulare Neurobiologie Hamburg, Falkenried 94, D-20251 Hamburg, Germany.

    • Melitta Schachner
  3. Keck Center for Collaborative Neuroscience and Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854, USA.

    • Melitta Schachner
  4. Department of Biochemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.

    • Peter Sonderegger

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Correspondence to Alexander Dityatev.

Glossary

NPxY motif

A peptide motif with the amino acid sequence Asn–Pro–any amino acid–Tyr, which is important for protein–protein interactions.

Sensorimotor gating of the startle reflex

Inhibition of the startle reflex by a weak 'prepulse' stimulus that occurs 30–500 ms before the startling stimulus.

Reversal learning

The form of learning in which an organism shifts its response from a stimulus that is no longer rewarded to a previously unrewarded one.

Dendritic spine

A small protrusion of the dendritic membrane that represents the postsynaptic component of the majority of the excitatory synapses in the CNS.

RGD peptide

A peptide containing a motif with the amino acid sequence Arg–Gly–Asp. Such motifs in extracellular matrix proteins are important activators of integrin signalling.

Perineuronal nets

Aggregates of extracellular matrix molecules that embed cell bodies, axon initial segments and proximal dendrites of a subset of neurons in a mesh-like structure.

Focal adhesion

A large, dynamic protein complex through which the actin cytoskeleton of a cell connects to the extracellular matrix through integrins, providing a cell anchor and a sensor of extracellular signals.

Membrane ruffles

Processes that are formed by the movement of lamellipodia in the dynamic process of folding back onto the cell body from which they have extended.

Theta burst stimulation

Several bursts of high-frequency (for example, 100Hz) stimulation, which are delivered at 5 Hz to mimic the hippocampal theta rhythm that is thought to be important for learning and memory.

Granule cell

A tiny neuron found in specific brain areas, including the dentate gyrus, where it is the principle excitatory neuron.

Extinction memory

The memory that is formed when an animal learns that a conditioned stimulus no longer predicts a harmful stimulus.

Memory reconsolidation

The process in which previously consolidated memories are recalled and then actively consolidated, leading to their preservation.

Early and late LTP

Long-term potentiation (LTP) may be subdivided into an early phase, which lasts up to 3 hours, and a later phase, which follows the early one and may last days to months. The extension of early into late LTP requires gene transcription and protein synthesis.

Dendritic filopodium

A thin and 'headless' membrane protrusion that is not strictly part of a synapse but serves as a precursor of new dendritic spines during activity-dependent synaptogenesis.

Hebbian learning

The strengthening of synaptic connections when the presynaptic and the postsynaptic neuron are active simultaneously, which is often summarized as 'cells that fire together, wire together'.

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https://doi.org/10.1038/nrn2898

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