Here we report that synapses in the adult dorsal vagal complex, a gateway for many primary afferent fibers, express a high level of the polysialylated neural cell adhesion molecule (PSA-NCAM). We show that electrical stimulation of the vagal afferents causes a rapid decrease of PSA-NCAM expression both in vivo and in acute slices. Inhibition of NMDA receptor activity completely prevented the decrease. Blockade of calmodulin activation, neuronal nitric oxide (NO) synthase, or soluble guanylyl cyclase and chelation of extracellular NO mimicked this inhibition. Our data provide a mechanistic framework for understanding how activity-linked stimulation of the NMDA-NO-cGMP pathway induces rapid changes in PSA-NCAM expression, which may be associated with long-term depression.