Cadherin-based transsynaptic networks in establishing and modifying neural connectivity

Abstract

It is tacitly understood that cell adhesion molecules (CAMs) are critically important for the development of cells, circuits, and synapses in the brain. What is less clear is what CAMs continue to contribute to brain structure and function after the early period of development. Here, we focus on the cadherin family of CAMs to first briefly recap their multidimensional roles in neural development and then to highlight emerging data showing that with maturity, cadherins become largely dispensible for maintaining neuronal and synaptic structure, instead displaying new and narrower roles at mature synapses where they critically regulate dynamic aspects of synaptic signaling, structural plasticity, and cognitive function. At mature synapses, cadherins are an integral component of multiprotein networks, modifying synaptic signaling, morphology, and plasticity through collaborative interactions with other CAM family members as well as a variety of neurotransmitter receptors, scaffolding proteins, and other effector molecules. Such recognition of the ever-evolving functions of synaptic cadherins may yield insight into the pathophysiology of brain disorders in which cadherins have been implicated and that manifest at different times of life.

Keywords: Cell adhesion molecules; Cognition; LTP; N-Cadherin; Neural development; Protocadherins; Synaptic plasticity.

Figure 1

Cadherin-8 is synaptically localized in striatum. This electron micrograph was taken from a section through the dorsal striatum of a P30 mouse that had been processed for immunogold localization of cadherin-8. The gold particles are clustered on both presynaptic (pre) and postsynaptic (post) sides of the asymmetric synapse (arrows), consistent with homophilic recognition, and this is a pattern of localization that is typical for classic cadherins in the brain. Bar, 100 nm.

Figure 2

Schematic diagram showing how the cadherin/catenin system can bidirec-tionally regulate synaptic plasticity by differentially controlling GluR subunit trafficking and/or stability at the surface. (A) During LTP, a synapse (top) becomes strengthened (wild-type synapse, bottom middle) by the insertion of GluRs into the membrane (small arrow in the spine head) and also undergoes a coordinated increase in the size of the spine head. N-Cadherin facilitates both processes by trapping and/or promoting GluR positioning through direct ectodomain interactions as well as through linkage to the actin cytoskeleton. In the case of the conditional N-cadherin deletion mutant (bottom left synapse), GluRs fail to insert and/or fail to become trapped at the synapse in the absence of N-cadherin (blocked arrow), thus persistent LTP and spine enlargement are both abolished. GluR endocytocis is presumably unaffected (small arrow), thus accounting for normal LTD in these mice. In the case of the cadherin/β-catenin stabilized mice (bottom right synapse), excessively stabilized surface N-cadherin has no effect on GluR insertion (small arrow), thus accounting for normal LTP in these mice. However, the surface-stabilized N-cadherin abnormally traps synaptic GluRs, thus preventing GluR endocytocis (blocked arrow) and blocking LTD. (B) During LTD, wild-type synapses (middle bottom) undergo endocytocis of both N-cadherin and GluRs from the synaptic surface (small arrows). In the N-cadherin conditional KO synapse (left synapse), GluR endocytocis is presumably not affected, thus yielding normal LTD. In contrast, when N-cadherin is surface stabilized (right synapse), GluRs are abnormally trapped, preventing endocytocis, thus these synapses fail to exhibit LTD. This cartoon is based on the studies of Bozdagi et al. (2010), Mills et al. (2014), and Nikitczuk et al. (2014).