A Model for Central Synaptic Junctional Complex Formation Based on the Differential Adhesive Specificities of the Cadherins

Abstract

Cadherins control critical developmental events through well-documented homophilic interactions. In epithelia, they are hallmark constituents of junctions that mediate intercellular adhesion. Brain tissue expresses several cadherins, and we now show that two of these, neural (N)- and epithelial (E)-cadherin, are localized to synaptic complexes in mutually exclusive distributions. In cerebellum, N-cadherin is frequently found associated with synapses, some of which are perforated, and in hippocampus, N- and E-cadherin-containing synapses are found aligned along dendritic shafts within the stratum lucidum of CA3. We propose that the cadherins function as primary adhesive moieties between pre- and postsynaptic membranes in the synaptic complex. According to this model, once neurites have been guided to the vicinity of their cognate targets, it is the differential distribution of cadherins along the axonal and dendritic plasma membranes, and ultimately cadherin self-association, that "locks in" nascent synaptic connections.

N-Cadherin Transsynaptically Regulates Short-Term Plasticity at Glutamatergic Synapses in Embryonic Stem Cell-Derived Neurons

“…In the developing brain, cadherins have been implicated in growth cone guidance and target recognition (Matsunaga et al, 1988;Inoue and Sanes, 1997;Sanes and Yamagata, 1999;Redies, 2000;Clandinin and Zipursky, 2002;Poskanzer et al, 2003). Classical cadherins localize to CNS synapses at perisynaptic sites (Fannon and Colman, 1996;Uchida et al, 1996) in the vicinity of the active zone and the postsynaptic density (Uchida et al, 1996;Phillips et al, 2001). N-cadherin is well known to be expressed at cortical glutamatergic synapses in mammals (Benson and Tanaka, 1998;Huntley and Benson, 1999).…”

N-Cadherin Juxtamembrane Domain Modulates Voltage-Gated Ca2+Current via RhoA GTPase and Rho-Associated Kinase

“…N-cadherin is a cell adhesion molecule (Takeichi, 1990) abundantly localized to the synaptic complex, where it forms adherens-like junctions adjacent to or fused to both the active zone and postsynaptic density (Fannon and Colman, 1996;Uchida et al, 1996;Brusés, 2000). These junctions participate in neuronal physiology in that activity-dependent potentiation of synaptic transmission is correlated with the strengthening of cadherin-mediated adhesion Tanaka et al, 2000).…”

β-Catenin regulates excitatory postsynaptic strength at hippocampal synapses

“…The best studied among such proteins are the classical cadherins, homophilic Ca 2ϩ -dependent adhesion molecules, which also play a role in axon outgrowth (13,14), dendrite arborization (15), and target recognition (16). Whereas the extracellular domain of cadherins provides the direct intercellular link between apposing cells, strong adhesion by cadherins requires the dynamic intracellular connection to the actin cytoskeleton through ␤-and ␣-catenins (17,18).…”