The induction of gene expression has been correlated with long-lasting neuronal plasticity and long-term memory (LTM) formation. The fast activation of constitutive transcription factors by signaling mechanisms is thought to be the link between synaptic events and gene expression. However, only one constitutive transcription factor, CREB, has been shown to play a key role in several memory paradigms, both in vertebrates and invertebrates. Here, we report evidences for Rel/NFkappa-B constitutive transcription factors participation in memory. Using the LTM paradigm in the crab Chasmagnathus, an enhancement of NFkappa-B DNA-binding activity was found after spaced training, which induces LTM, but not after massed training which yields an intermediate-term memory (ITM). Such finding is correlated with the requirement of protein synthesis for LTM consolidation but not for ITM. Furthermore, NFkappa-B activation was observed after 15 or 30 training trials, which are sufficient to induce LTM, but not after 5 or 10 trials, a number of trials insufficient to induce LTM. The kinetics of activation was studied and two waves of DNA-binding activity were found, similar to the time course described in other systems. NFkappa-B activation after training was also found in synaptosomal extracts. The latter result supports the hypothesis of a novel synapse-to-nucleus signaling system, in which the transcription factor is locally activated by synaptic events and then transported to the nucleus.