Synapse adhesion: a dynamic equilibrium conferring stability and flexibility

Cell adhesion molecules (CAMs) linked to cytoskeleton generate stable cell–cell junctions. Cadherins provide a canonical example, but paradoxically, they participate in a multitude of transient and regulatable interactions. Their extracellular binding generates weak adhesion that is modified by clustering; interactions with F-actin are regulated, can be transient, and can alter F-actin dynamics. Additionally, cadherin recycling from the cell surface can modify the size and location of junctions and strength of adhesion. In epithelial cells, this ongoing dynamic behavior is important for maintaining stable junctions. Recent work supports that cadherins act similarly at synapses where their actions are likely to be shared by integrins and other actin-linked CAMs. Together the collaborative activities of such CAMs provide a stable, but flexible structure that can promote and support changes in synapse shape and size while maintaining stable junctions to permit information flow.

Introduction

Synapses evolved to transfer information within networks of neurons and other cells. Information flows principally by a sequence of presynaptic membrane depolarization, neurotransmitter release and diffusion, and postsynaptic activation of neurotransmitter receptors, but can also occur through the exchange of growth factors, peptides and by cell-to-cell contact-mediated signals. Out of the recognition of this primary function grew the concept that synapse adhesive structure evolved mostly to provide a passive support, perhaps more sophisticated than glue, but nevertheless a relatively simple strut-like scaffold maintaining a constant gap separating rigidly parallel synaptic membranes. Here, the synapse, with its adhesive struts, can be viewed as two shorelines separated by a one-way bridge that allows vehicles (information) to travel across.

Synapses also store information over long periods, and they do this, in part, by changes in overall size or shape of postsynaptic dendritic spines, or by incorporating perforations or evaginations [1, 2••, 3••, 4]. This makes a bridge analogy insufficient. In order to change shape while maintaining information transfer, a stable, but flexible structure is required in which proteins, membranes, and cytoskeletal support networks can be added or removed without jeopardizing communication. Here, we propose that this basic structure can be provided by cell adhesion molecules (CAMs) linked to F-actin cytoskeleton.

A variety of adhesion proteins are found at synapses. Many of those identified can initiate synapse formation, customarily demonstrated by an ability to generate artificial synapses between CAM-expressing non-neuronal cells or CAM-coated beads and neurons [5]. Synaptogenic CAMs include presynaptic neurexins which can bind to postsynaptic neuroligins, LRRTMs, or a complex of cerebellin1 and gluRdelta2, presynaptic netrin Gs and LAR protein tyrosine phosphatase receptors which bind to postsynaptic netrin G ligands, presynaptic latrophilin 1 and postsynaptic teneurin-2, ephB interactions with ephrin-Bs, homophilic binding between synCAMs, and interactions between as yet unidentified presynaptic partners and postsynaptic SALMs. It is not known how many of each of these families are co-expressed at synapses, whether they act competitively, or cooperatively. However, in-depth analyses indicate that particular pairs impart unique synaptic features, supporting the idea that CAMs can act cooperatively. Synaptogenic CAMs typically bind PDZ proteins rather than F-actin. Because these have been the subjects of several recent reviews [6, 7, 8, 9, 10], they will not be discussed in depth here. Instead, in this review, we focus on the nature of synapse adhesion and the contributions of non-synaptogenic, actin-linked CAMs to the generation and maintenance of synapse adhesive structure (Figure 1). The focus is on cadherins, but much of what is covered is equally applicable to the integrin family.