We investigated the rat brain for the presence and activation state of the inducible transcription factor NF-kappa B. Two forms of NF-kappa B containing the transactivating p65 subunit were found in all brain regions investigated. The majority of NF-kappa B was in an inducible cytoplasmic form by virtue of its association with the inhibitory subunit I kappa B. Significant amounts of inducible NF-kappa B forms were present in synaptosomes, as suggested by electrophoretic mobility shift assay and Western blot analysis of subcellular brain fractions. A synaptic localization of NF-kappa B was further evident from immunostaining of inner and outer plexiform layers of the retina with an antibody directed against the p50 subunit of NF-kappa B. In cerebral cortex and striatum, NF-kappa B-specific antibodies showed a punctate immunostaining partially overlapping with that for the synaptic marker protein synaptophysin. NF-kappa B is thus the first transcription factor found in synapses of neurons. With its unusual subneuronal localization, the inducible transcription factor has the potential to function as retrograde messenger mediating stimulus-response coupling and long-term changes in gene expression following presynaptic stimulation.