Ca²⁺-regulated gene transcription is essential to diverse physiological processes, including the adaptive plasticity associated with learning. We found that basal synaptic input activates the NF-κB transcription factor by a pathway requiring the Ca²⁺/calmodulin-dependent kinase CaMKII and local submembranous Ca²⁺ elevation. The p65:p50 NF-κB form is selectively localized at synapses; p65-deficient mice have no detectable synaptic NF-κB. Activated NF-κB moves to the nucleus and could directly transmute synaptic signals into altered gene expression. Mice lacking p65 show a selective learning deficit in the spatial version of the radial arm maze. These observations suggest that long-term changes to adult neuronal function caused by synaptic stimulation can be regulated by NF-κB nuclear translocation and gene activation.