Ca2+-dependent adhesion molecules, cadherins, localised at synaptic sites are critically involved in long-term potentiation (LTP). N-cadherin is thought to promote LTP whereas cadherin-11 seems to counteract LTP. Since high synaptic activity is accompanied by local transient changes of the pH in the synaptic cleft, we studied whether the binding activity of cadherins is dependent on the pH and whether this might play a role during LTP. By atomic force microscopy (AFM) and laser tweezer experiments, we could show on the single molecule level as well as in a cell-based system that a decrease of the pH from 7.4 to 7.0 will result in a significant weakening of N-cadherin binding activity but in an increase of cadherin-11 binding. These differences in the pH dependencies of both molecules could be one explanation for their opposing roles during LTP. High-frequency stimulation will lead to a local acidosis in the synaptic cleft resulting in weakening of N-cadherin-mediated adhesion facilitating synaptic remodeling and LTP induction, whereas cadherin-11 bonds will be strengthened counteracting synaptic remodeling and LTP generation. Synapse 67:705–715, 2013. © 2013 Wiley Periodicals, Inc.