HDAC6 Inhibition Drives Synaptic Protein Acetylation and Enhances Long-Term Memory in Mice

Histone deacetylase inhibitors are known to influence memory consolidation, with synaptic protein acetylation playing a crucial role in plasticity processes such as long-term potentiation (LTP). In this study, we explored the role of non-histone protein acetylation in the consolidation of long-term inhibitory avoidance (IA) memory. We found that the histone deacetylase 6 (HDAC6) inhibitor, Tubastatin A, significantly enhanced memory consolidation when administered either intraperitoneally or directly into the hippocampus immediately after memory acquisition, but not when administered three hours later. Tubastatin A also preserved tubulin acetylation in hippocampal extracts in vitro and induced an increase in acetylation levels in vivo. Training in the IA task led to alterations in tubulin acetylation within synaptic extracts, specifically at residues other than lysine 40 of α-tubulin, accompanied by changes in synaptic composition. Furthermore, chemical LTP in primary hippocampal neuron cultures increased dendritic and synaptic acetylation, as well as the density of PSD95 clusters. These findings establish a role for HDAC6 in modulating tubulin acetylation during memory consolidation and provide new insights into the broader significance of non-histone protein acetylation in memory formation.