The structure and function of synapses are highly heterogeneous, even among synapses formed on single neurons. Several lines of evidence suggest that presynaptic functionality is regulated retrogradely via mechanisms involving postsynaptic components. One potential class of candidate proteins mediating such trans-synaptic modulation are cell adhesion molecules that can coordinate signaling events across the synaptic cleft. In particular, N-cadherin/b-catenin complex is a Ca2+-dependent homophilic adhesion protein with established roles in controlling synapse formation and dendritic spine morphology. We have tested whether the postsynaptic N-cadherin/b-catenin complex modulates presynaptic release. Using FM dyes to monitor synaptic vesicle turnover in cultured hippocampal neurons, impairing the adhesion of N-cadherin by postsynaptic overexpression of a dominant negative form of this protein reduces the release probability, the ready-releasable pool and the recycling pool of synaptic vesicles. However, preliminary studies suggest that chronic activity manipulations do no affect the ability of these neurons to undergo adaptive scaling of presynaptic release probability. Our results indicate that the postsynaptic N-cadherin/b-catenin complex is an important modulator of presynaptic release probability and plays a basic role in linking presynaptic and postsynaptic functions.