HDAC3 inhibitor RGFP966 acts on the NF-kB pathway and enhances memory persistence in a biphasic manner

Nearly five decades ago, it was first observed that long-term memory consolidation requires waves of transcriptional activity and protein synthesis, with the first two waves occurring within hours after learning. While numerous studies have examined the effects of protein synthesis inhibitors, the contribution of epigenetic mechanisms in these waves remains poorly understood. Here, we aimed to determine the role of HDAC3, a key modulator of memory, in these two phases of gene expression, as well as its functional link with the transcription factor NF-{kappa}B, one of its deacetylation targets, and a critical player in memory formation. Pharmacological inhibition of HDAC3 with RGFP966, either immediately or 6 hours after training, enhanced memory persistence in the NOR task in mice. Conversely, inhibition of NF-kB with BAY 11-7082 impaired memory at the same time points. Moreover, RGFP966 injection increased the nuclear proportion of NF-{kappa}B in the CA1 region of the hippocampus, suggesting a functional link between HDAC3 activity and NF-{kappa}B nuclear translocation. To our knowledge, this study provides the first in vivo evidence of this relationship during memory consolidation, extending previous findings from cell culture and electrophysiological studies in brain slices.