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Integrins in synapse regulation

Key Points

  • Integrins are major cell surface receptors for the extracellular matrix (ECM). Intracellularly, integrins link to the actin cytoskeleton and signalling systems and thus function as mechanochemical signal transducers between the extracellular environment and the cell.

  • Integrins are heterodimers of α- and β-subunits, and many integrin subtypes are expressed in the brain. During development, integrins have multifaceted roles in differentiation and maintenance of neural stem cells, axon outgrowth and dendrite arborization, in concert with signalling involving the ECM, growth factor receptors and adhesion proteins.

  • Synaptic integrins detect dynamic changes in the extracellular synaptic milieu and coordinate synapse structure and function. Integrins regulate synapse formation and maturation, in concert with glial signals, regulate postsynaptic strength by controlling neurotransmitter receptor dynamics and alter dendritic spine shape by triggering actin remodelling.

  • Different integrin subtypes participate in distinct forms of synaptic plasticity. Presumably, the differences reflect the differences in their biophysical properties, molecular interactors and signalling systems to which they are linked under specific cellular contexts.

  • The differential expression pattern of the integrin subtypes may also provide the basis for the subtle differences in behavioural phenotypes that are associated with mice deficient in particular subtypes of integrin. In the hippocampus, β1-containing integrins are required for working memory, whereas β3-containing integrins seem to be involved in emotional behaviours.

  • Much remains to be clarified about the basic properties of synaptic integrins, including the detailed cellular and subcellular expression of each of the subtypes in different brain regions and in circuits underlying specific behaviours, the native extracellular ligands of synaptic integrins and their dynamic regulation modulated by ECM remodelling, and the interactions of synaptic integrins with other binding partners within and outside synapses.

Abstract

Integrins are a large family of extracellular matrix (ECM) receptors. In the developing and adult brain, many integrins are present at high levels at synapses. The tetrapartite structure of synapses — which comprises presynaptic and postsynaptic neurons, the ECM and glial processes — places synaptic integrins in an excellent position to sense dynamic changes in the synaptic environment and use this information to coordinate further changes in synapse structure and function that will shape neural circuit properties. Recent developments in our understanding of the cellular and physiological roles of integrins, which range from control of neural process outgrowth and synapse formation to regulation of synaptic plasticity and memory, enable us to attempt a synthesis of synaptic integrin function.

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Figure 1: Integrin functions are associated with every component of the tetrapartite synapse.
Figure 2: Integrin activation and signalling.
Figure 3: AMPA receptor regulation by β3-containing integrins.

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Acknowledgements

The authors thank T. Chater and P. Chipman for critical reading of the manuscript. Research in the authors' laboratory is supported by the RIKEN Brain Science Institute, the Japan Society for the Promotion of Science (JSPS) Core-to-Core Program, Grants-in-Aid for Scientific Research (15H04280) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), and the Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS) from the Japan Agency for Medical Research and Development (AMED).

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Correspondence to Yukiko Goda.

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PowerPoint slides

Glossary

Counter receptors

Molecules that bind to cell surface receptors. Counter receptors for integrins include neural cell adhesion molecule L1 (NCAML1) and vascular cell adhesion protein 1 (VCAM1), which themselves are cell surface proteins.

Adaptor proteins

Molecules containing distinct modular domains that typically mediate protein–protein interactions and allow these proteins to form signal transduction complexes.

Perineuronal nets

Specialized extracellular matrix structures that surround the somata and proximal dendrites of certain neuron types. They are important for synaptic stabilization and have been suggested to be crucial for the closure of critical periods.

Synaptic dwell time

The amount of time during which a diffusible molecule remains inside the synapse.

Focal adhesion sites

Specialized sites of adhesive contact where integrins link the extracellular matrix to intracellular signalling complexes and to the actin cytoskeleton.

Long-term potentiation

(LTP). A long-lasting (hours or days) increase in the response of neurons to stimulation of their afferents following a brief patterned stimulus (for example, a 100 Hz stimulus train).

Long-term depression

(LTD). A long-lasting decrease in the response of neurons to stimulation of their afferents following a brief patterned stimulus (for example, a 1 Hz stimulus train).

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Park, Y., Goda, Y. Integrins in synapse regulation. Nat Rev Neurosci 17, 745–756 (2016). https://doi.org/10.1038/nrn.2016.138

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