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, how specific epigenetic regulators contribute to these waves remains poorly understood. Here, we aimed to determine whether HDAC3, a key modulator of memory, is involved in memory consolidation at these two time points through its potential relationship with the transcription factor NF-kB, 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 that HDAC3 inhibition is associated with changes in NF-kB nuclear localization. To our knowledge, this study provides the first in vivo evidence that HDAC3 inhibition is associated with altered NF-kB localization during memory consolidation, extending previous observations from cell culture and electrophysiological studies in brain slices. Although these findings support a functional association between HDAC3 inhibition and NF-kB signaling during consolidation, further experiments will be required to determine whether this relationship is mechanistically causal.