Cadherins and catenins at synapses: roles in synaptogenesis and synaptic plasticity

doi:10.1016/j.tins.2008.07.001

Trends in Neurosciences

Volume 31, Issue 9, September 2008, Pages 487-494

https://doi.org/10.1016/j.tins.2008.07.001 Get rights and content

Synapse formation involves reciprocal interactions between cells resulting in formation of a structure optimized for efficient information transfer. Recent work has implicated constituents of the cadherin–catenin cell-adhesion complex in both synapse formation and plasticity. In this review, we describe recent interesting discoveries on mechanisms of cadherin complex function, in addition to regulating adhesion, that are relevant for understanding the role of this complex in synaptogenesis and plasticity. We describe how this complex acts via (i) recruitment/stabilization of intracellular partners; (ii) regulation of intracellular signaling pathways; (iii) regulation of cadherin surface levels, stability and turnover; (iv) stabilization of receptors; and (v) regulation of gene expression. These exciting discoveries provide insights into novel functional roles of the complex beyond regulating cell adhesion.

Introduction

Synapses of the central nervous system are specialized asymmetric cell-adhesion junctions that mediate directional information transfer. Pre- and postsynaptic compartments are morphologically distinct with specialized functional roles. Presynaptic terminals contain synaptic vesicles and machinery for neurotransmitter release, whereas postsynaptic sites include neurotransmitter receptors and a variety of scaffolding and signaling proteins. Together, these molecules ensure rapid and directional information transfer. Moreover, the synaptic compartments are dynamic, allowing for synaptic modulation in response to neural activity, a property believed to underlie the ability of the nervous system to learn and retain memory 1, 2. The processes that underlie synapse assembly, maintenance and plasticity need to be precisely regulated during development and in response to synaptic activity to optimize functioning of synapses and neural circuits.

In this review, we focus on the role of a cell-adhesion complex, the cadherin–catenin complex, in synapse morphogenesis and plasticity within the mammalian central nervous system. This complex has been extensively studied in epithelial cells. It is becoming increasingly clear that it also has very interesting functional roles in neurons. Several studies indicate that components of the complex regulate multiple aspects of synapse morphogenesis and plasticity. Many of the insights obtained in epithelia concerning mechanisms through which adhesion and signaling by the cadherin complex are regulated appear to be useful in understanding the functions of these complexes in synapse formation, function and plasticity [3].

Section snippets

Contact-mediated adhesion in synaptogenesis

The formation of a synapse requires target recognition followed by recruitment of pre- and postsynaptic elements in precise apposition (Figure 1). Synapse morphogenesis is initiated by formation of contacts between filopodia that arise from dendrites and axon segments, followed by contact stabilization and acquisition of appropriate pre- and postsynaptic elements, together with spine maturation at many excitatory synapses. Synaptic maturity is characterized by morphological and molecular

The cadherin–catenin cell-adhesion complex

The cadherin family is composed of more than 80 members in a single species that has been classified into several subfamilies, including classical cadherins, protocadherins, Fat cadherins, CNRs and seven-pass transmembrane cadherins [7]. This review is restricted to classical cadherins. The roles for cadherins and catenins, cytosolic partners of cadherins, in regulating cell adhesion in epithelial cells have been extensively explored. It is now clear that these proteins regulate synaptogenesis

The cadherin–catenin complex at central synapses

Multiple cadherins are expressed in the central nervous system [16] with distinct spatial and temporal expression patterns. Our understanding of the contribution of specific cadherins to synapse development and maintenance remains incomplete, in part because many neurons express more than one cadherin.

The most widely distributed neuronal cadherin is N-cadherin, whose distribution changes during development [7]. At young hippocampal synapses in culture (DIV [days in vitro] 5–6), N-cadherin is

The cadherin–catenin complex in excitatory synapse morphogenesis and plasticity

In neurons, the cadherin–catenin cell-adhesion complex regulates multiple aspects of synaptogenesis and plasticity. Interestingly, several recent studies have examined the mechanistic bases of these functional roles. Cadherins are well suited to promote adhesive functions and, by virtue of association with catenins, link cell adhesive interactions to a variety of intracellular pathways. The effects of the loss or overexpression of the cadherins and catenins are summarized in Table 1.

Cadherins

The cadherin–catenin complex in inhibitory synaptogenesis

Relatively less is known about the functional roles of the cadherin complex in the development and maintenance of inhibitory synapses. N-cadherin is excluded from inhibitory synapses during development in hippocampal neurons [21]. It is unclear whether N-cadherin is replaced by another cadherin and what the contribution of this cadherin is to inhibitory synaptogenesis. Cadherin-11 and -13 promote the formation of inhibitory synapses in cultured hippocampal neurons [65]. The roles of the

The cadherin–catenin complex in human neurological disease

Dendrite and spine abnormalities are associated with several human conditions, including mental retardation, normal aging process and neurodegenerative disorders. Given their wide expression pattern and their critical roles in synapse and spine morphogenesis and plasticity, it is highly likely that mutations in cell-adhesion molecules might underlie several neurological disorders.

There is currently no direct evidence for the involvement of a specific mutation of any of the components of the

Conclusions and future directions

It is clear that the cadherin–catenin complex is pivotal in spine and synapse morphogenesis and plasticity, with each component of the complex making a contribution. No doubt, technical advances in genomics and proteomics will greatly aid in identifying more novel interaction partners for the complex and increase our understanding of the multiple and complex functional roles of this complex in neurons.

However several questions remain. What signaling pathways are regulated by the

Conflict of interest statement

The authors declare no competing financial interests.

Acknowledgements

J.A. is supported by a postdoctoral fellowship from the Larry L. Hillblom Foundation. We also thank Seung-hye Lee for comments on the manuscript and Dr. Baris Genc for assistance with the figures. Work in the authors’ laboratory is supported by the National Institutes of Health.

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Trends in Neurosciences

ReviewCadherins and catenins at synapses: roles in synaptogenesis and synaptic plasticity

Introduction

Section snippets

Contact-mediated adhesion in synaptogenesis

The cadherin–catenin cell-adhesion complex

The cadherin–catenin complex at central synapses

The cadherin–catenin complex in excitatory synapse morphogenesis and plasticity

The cadherin–catenin complex in inhibitory synaptogenesis

The cadherin–catenin complex in human neurological disease

Conclusions and future directions

Conflict of interest statement

Acknowledgements

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Review
Cadherins and catenins at synapses: roles in synaptogenesis and synaptic plasticity