Cellular And Subcellular Localization And Trafficking During Terminal Outgrowth And Synaptogenesis

Several individual cadherins are expressed reciprocally by afferent and target regions5. These findings have lent support to the concept of a cadherin code whereby cadherins, acting individually or in combination, impart specificity to synapse targeting and maturation. This notion is supported further by cases of mutual exclusion, such as the localization of N-cadherin and cadherin-8 to synapses in developing rat somatosensory cortex according to their respective thalamic nuclei of origin, and N- and E-cadherin immunolabeling in adult hippocampus1,27. The time course for such actions may be protracted, as n-cadherin is initially present at all synapses between hippocampal neurons and gradually becomes excluded from GABAergic sites as neurons mature28.

As the rat hippocampus develops, immunogold-labeled cadherins are widely and regularly distributed along the synaptic cleft of young synapses, supporting the idea that cadherins are major contributors to adhesion at young synaptic junctions. The even distribution also suggests a possible role in matching pre- to postsynaptic size. Over the course of maturation, cadherins become concentrated in clusters that can be localized within or just outside of the active zone29. In adult mouse cerebellum, immunogold labeling for an- and P-catenins, presumably bound to the cytoplasmic tail of cadherins, is concentrated in clusters similar to those seen in hippocampus, but localized exclusively at the edges of synaptic active zones suggesting that the adult distribution of cadherins within synapses may differ slightly between brain areas2. More importantly, the data suggest that the functions of cadherins differ between newly formed synaptic junctions and more mature sites.

Most studies of the synaptic localization and trafficking of individual cadherins have focused on n-cadherin. Prior to synaptogenesis, n-cadherin is concentrated in vesicle-like particles in axonal and dendritic cytoplasm28. At least some of these particles correspond to the large dense-core vesicles that also transport Bassoon, RIM, and other essential components to nascent synapses30,31. Live images of fluorescently tagged n-cadherin in developing zebrafish show the deposition of protein from an intracellular pool at nascent axon terminals of spinal Rohon-Beard neurons. Deletion of the extracellular domain, but not the cytoplasmic tail, occludes this synaptic accumulation32, suggesting that n-cadherin becomes targeted to presynaptic terminals during exocytosis or by lateral membrane diffusion and trapping. As with E-, and P-cadherins, n-cadherin has been identified in postsynaptic fractions purified from adult rat forebrain33-35. The presence of n-cadherin at both sides of the synapse is consistent with the presumed trans-synaptic binding and function of cadherins.

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