Two forms of activity-dependent long-term depression (LTD) in the CNS, as defined by their sensitivity to the blockade of NMDA receptors, are thought to be important in learning, memory, and development. Here, we report that NMDA receptor-independent LTD is the major form of long-term plasticity in the anterior cingulate cortex (ACC). Both L-type voltage-gated calcium channels and metabotropic glutamate receptors are required for inducing LTD. Amputation of a third hindpaw digit in an adult rat induced rapid expression of immediate early genes in the ACC bilaterally and caused a loss of LTD that persisted for at least 2 weeks. Our results suggest that synaptic LTD in the ACC may contribute to enhanced neuronal responses to subsequent somatosensory stimuli after amputation.