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Cell adhesion molecules: signalling functions at the synapse

Key Points

  • Cell adhesion molecules are present at synaptic sites throughout the lifetime of a synapse and are involved in the formation, function and plasticity of synaptic connections.

  • Synaptically localized cell adhesion molecules (SAMs), are multifunctional molecules that coordinate different aspects of synaptic development and function through specialized signalling or protein–protein interaction motifs.

  • Neurexin–neuroligin signalling has a role in the development of pre- and postsynaptic terminals at both excitatory and inhibitory synapses. Recent in vivo data indicates that these molecules are most important for the proper maturation and function of synaptic contacts.

  • The EphB receptor tyrosine kinase regulates excitatory synaptogenesis, including the clustering of NMDARs (N-methyl-D-aspartate receptors) and AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors), dendritic spine formation and presynaptic differentiation. EphB-mediated signalling seems to be particularly significant for a subset of synaptic inputs in vivo.

  • A number of molecules belonging to the immunoglobulin superfamily of proteins (synaptic cell adhesion molecule (SynCAM), synaptic adhesion-like molecule (SALM) and netrin G2 ligand (NGL2)) also contain intracellular PDZ binding domains that permit interactions with the postsynaptic scaffold protein PSD-95 (postsynaptic density protein-95). Each of these trans-synaptic signals can control aspects of excitatory synapse formation in vitro.

  • Cadherins signal via catenins to regulate dendritic spine morphology and motility. In addition, in vivo work has shown that the loss of particular catenin molecules results in abnormal synapse formation and/or maturation.

  • Ephs and ephrins regulate two mechanistically distinct forms of long-term potentiation in the hippocampus. At the mossy fibre–CA3 synapse this occurs downstream of a transynaptic interaction between postsynaptic EphB and presynaptic ephrin-B, whereas at the Schaeffer collateral–CA1 synapse the mechanism is less clear.

  • Multiple lines of evidence indicate that neural cell adhesion molecule and cadherin regulate hippocampal synaptic plasticity. Both molecules possess multiple adhesive and signalling functions that could be important for plasticity, but the exact mechanisms by which these molecules regulate these functions are not clear.

Abstract

Many cell adhesion molecules are localized at synaptic sites in neuronal axons and dendrites. These molecules bridge pre- and postsynaptic specializations but do far more than simply provide a mechanical link between cells. In this review, we will discuss the roles these proteins have during development and at mature synapses. Synaptic adhesion proteins participate in the formation, maturation, function and plasticity of synaptic connections. Together with conventional synaptic transmission mechanisms, these molecules are an important element in the trans-cellular communication mediated by synapses.

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Figure 1: Synaptic adhesion molecules function throughout the life of a synapse.
Figure 2: Neurexin–neuroligin splice code and synapse formation.
Figure 3: Trans-synaptic signalling during synaptogenesis: in vitro evidence.

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Acknowledgements

We thank L. Gabel for helpful comments. The authors work is supported by a Whitehall Foundation, Edward Mallinckrodt Jr Foundation, Philadelphia Foundation, and Mental Retardation Developmental Disability Research Center grant to M.B.D., the Training Program in Developmental Biology to A.C.M. and by the Ruth L. Kirschstein National Research Service Award to M.S.K.

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Glossary

Synapse formation

The initial contact of two neurons and organization of the earliest components of a young synapse, including presynaptic vesicles and release machinery, and postsynaptic NMDA receptors and PSD-95.

Synaptic plasticity

The ability of certain patterns of activity to lead to increases or decreases in synaptic strength.

Synaptogenesis

The entire process that leads to a fully functional synapse, including cell–cell contact, differentiation of nascent pre- and postsynaptic terminals, development of morphological specializations, and ultimately the organization of mature synaptic inputs.

Alternative splicing

The production of different proteins from the same RNA transcript by combining splice donor and acceptor sites in different combinations.

PDZ binding domain

Protein domains that typically bind specific carboxy-terminal sequences in target proteins. Many proteins contain one or more PDZ domains, which were named after the initial three members (PSD-95, Drosophila discs large protein and ZO-1).

Miniature synaptic current

The postsynaptic current evoked by release of a single vesicle of neurotransmitter — the quantal amplitude.

Synapse maturation

Expansion and stabilization of a synapse characterized by morphological maturation into a mushroom-shaped dendritic spine, additional recruitment of synaptic proteins necessary for plasticity such as AMPA receptors, and other events leading to normal synaptic transmission.

Adaptor protein

A protein that contributes to cellular function by recruiting other proteins to a complex. Such molecules often contain several protein–protein interaction domains.

Yeast two-hybrid screen

System used to determine the existence of direct interactions between proteins. Two hybrid proteins are expressed together in yeast; one is fused to the GAL4 DNA-binding domain and the other is fused to the GAL4 activation domain. If the proteins interact, the resulting complex drives the expression of a reporter gene, commonly β-galactosidase.

Basket cells

Inhibitory interneurons located in the molecular layer of the cerebellum. Basket cells are located close to Purkinje cells and are spread out horizontally.

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 neurotransmitter release.

Synaptic vesicle recycling

The process whereby synaptic vesicles release neurotransmitter, are reformed and refilled with neurotransmitter to be re-used in synaptic release.

Long-term potentiation

(LTP). The prolonged strengthening of synaptic inputs, which is induced by patterned input and is thought to be involved in learning and memory formation.

Long-term depression

(LTD). A persistent reduction of synaptic strength in response to weak, poorly correlated input.

Miniature synaptic potentials

Synaptic potentials observed in the absence of presynaptic action potentials; they are thought to correspond to the response elicited by a single vesicle of transmitter.

Morris water maze

A task used to assess spatial memory, most commonly in rodents. Animals use an array of extra-maze cues to locate a hidden escape platform that is submerged below the water surface. Learning in this task is hippocampus-dependent.

Synaptic puncta

The cluster of synaptic proteins labelled with antibodies raised against various synaptic marker proteins.

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Dalva, M., McClelland, A. & Kayser, M. Cell adhesion molecules: signalling functions at the synapse. Nat Rev Neurosci 8, 206–220 (2007). https://doi.org/10.1038/nrn2075

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