Molecular Mechanisms Of Cadherin Action During Synaptogenesis And Synaptic Function

How cadherins mediate synapse maturation and function is not well understood, but their associations with P- and 8-catenin and, thereby, the actin cytoskeleton, are considered prime modes of action (Figure 5.2). F-actin, like the cadherins, is required to assemble and maintain synapses in hippocampal neurons during the first week in culture45. By contrast, actin depolymerization with latrunculin A in mature cultures, where synaptogenesis is virtually complete, has no apparent effect on terminal density. PSD-95 clusters are not affected by depolymerization at any stage of maturation, but NMDA and AMPA receptor number and synaptic localization are susceptible to this treatment to varying degrees44,45, supporting a general requirement for actin-linked cell-adhesion molecules in maintaining synapse composition independent of PSD-95 scaffolding. Long-term blockade of cadherin-based adhesion occludes the F-actin independence of synapse maintenance normally attained in the third week of culture15,41. Stabilizing actin, in contrast, prohibits rundown and long-term depression (LTD) of NMDA receptor-mediated responses at maturing hippocampal synapses57,58. Cadherins and other cell-adhesion molecules conceivably achieve tight control of these F-actin dependent physiological properties under normal conditions. Cadherins also have been implicated in modulating glutamate receptor-dependent, actin-mediated spine dynamics54,59, perhaps in coordination with physiological properties.

Overexpression of either P-catenin or aN-catenin, as with N-cadherin, enhances dendritic arborization and spine maturation42,60. Conversely, the dendritic arbors of 3-week old hippocampal neurons from aN-catenin deficient mice are studded with elongated or spiky protrusions rather than spines15,41,42. While these and other observations implicate these catenins as direct mediators of cadherin function, care must be taken when dissecting the individual contributions of the several molecules that bind the cadherin intracellular domain (Figure 5.2) or ascribing their actions to cadherins. For instance, although the effects of P-catenin deletion on vesicle clustering are quite similar to those seen with cadherin blockade, its effect on synaptophysin trafficking does not appear to involve cadherins, as cadherins remain clustered at affected sites following P-catenin deletion14. Additionally, the principal effects of G-catenin on dendritic arborization appear to be mediated via the Wnt pathway and not through classic cadherins42. Modulation of high-voltage activated (HVA) calcium channels by the sJMD is counteracted by acute inactivation of either RhoA GTPase- or Rho-associated kinase, which similarly implicates these latter proteins as effectors of sJMD function, particularly through their functional interactions with p120 catenin23,52. Still, other binding partners of the sJMD, either cadherin-associated or in cytosolic pools, could contribute to its modulation of HVA channels. To dissect the functional contributions of individual binding partners unequivocally, conditional ablation of cadherins will be need to be combined with the conditional expression of mutated cadherins.

Other studies suggest that cadherins can influence synapse maturation and function independent of their interactions with the catenins and actin. n-, E-, and P-cadherins along with actin, several catenins, and the A-kinase anchoring protein AKAP79/150 previously have been found in large multiprotein complexes with the NMDA receptor34. Under more stringent conditions, the membrane-targeted

AKAP79/150, which also forms a complex with PSD-95, the GluR1 subunit of the AMPA receptor and the protein phosphatase calcineurin (PP2B), has been shown to bind noncompetitively with P-catenin to a site within the cadherin intracellular domain26,61,62 (Figure 5.2). Given the requirement of AKAP79 for PKA phosphorylation of the AMPA receptor, these biochemical findings collectively imply that mobilizing cadherins can have immediate effects on glutamate receptor function during developmental and adult plasticity. A presenilin-1-generated cleavage fragment of intracellular A-cadherin, which can bind CREB-binding protein and inhibit CREB-mediated transcription in non-neuronal cells12, may effect an additional, delayed modulation of synaptic strength in neurons.

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