Cadherins and synaptic plasticity Chin-Yin Tai , Sally A ...brain.mpg.de/fileadmin/user_upload/Documents/Papers/Papers_Schuman/Tai... · Available online at Cadherins and synaptic
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Available online at www.sciencedirect.com Cadherins and synaptic plasticity Chin-Yin Tai 1 , Sally A Kim 1 and Erin M Schuman Given their trans-synaptic localization, their persistent expression at mature synapses and their distinct biochemical and adhesive properties, cadherins are uniquely poised at the synapse to mediate synaptic plasticity, the ability to change synaptic function thought to underlie learning and memory. For example recent work suggests that cadherins may recruit and stabilize AMPA receptors at the synapse via direct interactions or through complex formation, revealing cross talk between postsynaptic signaling and adhesion. Moreover, the use of small interfering RNA knockdown of cadherin, the availability of N-cadherin-deficient embryonic stem cells and the acute disruption of cadherin function with peptide application in vivo have allowed for more precise dissection of the molecular mechanisms by which cadherins function in both structural and functional plasticity. Addresses Howard Hughes Medical Institute, Division of Biology, California Institute of Technology, 1200 East California Boulevard, Pasadena, CA 91125, USA Corresponding author: Schuman, Erin M ([email protected]), Tai, Chin-Yin ([email protected]) and Kim, Sally A ([email protected]) 1 These authors contributed equally to this work. Current Opinion in Cell Biology 2008, 20:567–575 This review comes from a themed issue on Cell-to-cell contact and extracellular matrix Edited by Mark Ginsberg and Jean Schwarzbauer Available online 19th July 2008 0955-0674/$ – see front matter Published by Elsevier Ltd. DOI 10.1016/j.ceb.2008.06.003 Introduction After the initial establishment of neuronal connections during development, synapses remain highly dynamic and undergo activity-dependent changes in efficacy and morphology. For over a century, this capacity to induce long-lasting changes in synaptic strength (‘synaptic plasticity’) has been considered the cellular basis of learn- ing and memory. Considerable effort has been made to identify the cellular mechanisms that trigger and stabilize synaptic changes over time. Adhesion molecules are known to participate in early stages of synapse formation and assembly [1–3]. However, it has become clear that the function of these molecules extends well beyond their developmental roles to encompass the capacity for dynamic regulation of synaptic strength in an analogous manner. Cadherins, in particular, possess qualities that dis- tinguish them from other adhesion molecules. Other adhesion molecules, such as neuroligins/neurexins and ephrin/Eph receptor complexes, interact with channel proteins and are thought to participate more in signaling events rather than adhesion [4]. Cadherins, on the other hand, have been shown to be involved in both adhesion via homophilic binding and signaling through binding interactions with other proteins or through protease- mediated cleavage. In neurons, cadherins are enriched at synapses and are localized at or near the synapse as revealed by confocal microscopy and at the ultrastruc- tural level by immunoelectron microscopy (Figure 1)[5– 8]. Structurally, ‘classic’ cadherins share a common highly conserved extracellular cadherin (EC) region comprising five tandem repeat domains followed by a single membrane-spanning region and a C-terminal intracellular tail (here the general term cadherin will refer to this family). Interestingly, the extracellular dimensions and orientation of the cadherins appear opti- mized to bridge the synaptic cleft between two neurons [4](Figure 1). Perhaps the most interesting feature of cadherins is the property of Ca 2+ -dependent adhesion. Upon binding of Ca 2+ , the molecule rigidifies, can dimerize and is stabil- ized. Furthermore, in the Ca 2+ bound, strong adhesive state, cadherin molecules acquire marked resistance to proteolytic degradation for extended periods of time [9,10]. In light of its Ca 2+ -dependence, it has been pro- posed that cadherins may transmit information about the local Ca 2+ dynamics across the synapse and induce trans- synaptic intracellular signaling [11]. Taken together, the properties of cadherins coupled with recent functional studies discussed here argue against a static structural role for cadherins. In this review, we discuss the modern view that cadherins mediate functional and structural plasticity. While sig- nificant progress over the past decade has successfully solidified the role of cadherins at the synapse, recent data in the past couple of years has advanced our understand- ing of cellular mechanisms of cadherins in regulating the function of cell adhesion and signaling in synaptic plasticity from the individual synapse up to the entire organism. Cadherins and extracellular Ca 2+ The extracellular domain of classic cadherins consists of five 110 amino acids repeats with three Ca 2+ -binding sites situated between each of these repeats [4]. Structural and biophysical studies suggest cadherin adhesive multimers www.sciencedirect.com Current Opinion in Cell Biology 2008, 20:567–575
