The neuronal immediate early gene Arc (also known as Arg3.1) is one of the most dynamically regulated genes in the brain and its induction is tightly linked to information processing in neuronal circuits. Arc plays critical roles in AMPA receptor (AMPA-R) trafficking, synaptic plasticity, experience-dependent cortical reorganization as well as long-term memory formation. It remains, however, paradoxical why Arc, which is upregulated by strong synaptic activity that induces persistent forms of plasticity and learning, also critically contributes to weakening synapses by promoting AMPA-R endocytosis during various forms of synaptic and homeostatic plasticity. Here we show a preferred targeting of Arc/Arg3.1 to inactive synapses. We found that this synaptic targeting of Arc was regulated by dynamic interaction between Arc and the inactive form of the beta isoform of CaMKII (CaMKIIβ). We also found that the degree of synaptic Arc/Arg3.1 accumulation was more sustained during a period of inactivity following strong induction, and correlated with removal of surface GluA1 from individual synapses. Taken together, we propose a novel "inverse" synaptic tagging mechanism that enables Arc to specifically target the un-potentiated synapses to promote the clearance of surface AMPA-R, thereby helping to maintain the contrast of synaptic weight between strengthened and weak synapses. and thus serving for consolidation of long-term memory.