Activity-dependent synaptic plasticity is widely accepted to provide a cellular basis for learning and memory. Synaptic associativity could be involved in activity-dependent synaptic plasticity, because it distinguishes between local mechanisms of synaptic tags and cell-wide mechanisms that are responsible for the synthesis of plasticity-related proteins (PRPs) . An attractive hypothesis for synapse specificity of long-term memory (LTM) is synaptic tagging: synaptic activity generates a tag, which captures the PRPs derived outside of synapses. Here we show that neuropsin, a plasticity-related extracellular protease, is engaged in synaptic tag setting for late associativity in vitro and behavioral tag setting for LTM in vivo. First, we investigated about neuropsin dependent late associativity using electrophysiological technique. Neuropsin was involved in synaptic tagging during LTP at basal and apical dendritic inputs. Furthermore we next addressed whether a neuropsin was involved in behavioral tag setting. Behaviorally, weak training, which induces short-term memory (STM) but not LTM, can be consolidated into LTM by exposing animals to novel but not familiar environment 1 h before training. We found that neuropsin deficient mouse impaired such transformation STM into LTM. These results suggest neuropsin as a tag setting for synaptic plasticity and memory.