Roles In Assembly Retention And Function Of Pre And Postsynaptic Components

a-cadherin expressing HEK293 cells fail to induce vesicle clusters in apposing hippocampal axons in heterologous cultures46. This finding, along with its targeting to nascent but pre-existing Rohon-Beard synapses32, suggests that a-cadherin is present from early stages but does not initiate synapse assembly by itself. However, several lines of evidence indicate that, beyond their morphogenetic actions, cadherins may dynamically influence the composition and function of maturing synapses. Overexpression of an extracellular domain deletion mutant in dissociated hippocampal neurons grown in culture for a week blocks synapse formation and retention completely. In more mature neurons transient expression of the same mutant reduces presynaptic terminal density generally, but also reduces GABAergic innervation to a lesser but significant extent15. Both excitatory and inhibitory terminal densities recover to normal levels with longer blockades, but active vesicle recycling, as visualized by styryl dye reuptake, is reduced41. Notably, mEPSCs recorded from these transfected neurons occur with lower frequency, indicating that presynaptic activity in untransfected neurons also is affected by the postsynaptic disruption and further supporting the notion that postsynaptic cadherins can act retrogradely via homophilic adhesion47,48. Postsynaptically, PSD95 clusters are smaller and fewer with transient pan-cadherin functional blockades in hippocampal neurons or following perturbation of cadherin-6B function in chick retinal neurons15,49. These latter observations imply that individual cadherins may either cluster or anchor particular synaptic components. Consistent with this potential role, beads coated with the a-cadherin extracellular domain can cluster GluR6-containing kainate receptors and ^-cadherin can recruit the MAGUK SAP97 to the cortical cytoskeleton in nonneuronal cell lines50,51, although it remains to be demonstrated whether these functions are served in neurons. In a separate vein, infusion of embryonic chick ciliary neurons with the intercellular juxtamembrane domain of .N-cadherin (sJMD) attenuates the amplitude of high-voltage activated calcium currents52. Thus, in addition to simply clustering synaptic components, cadherin interactions interactions may modulate channel surface expression or activity.

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