HDAC3 Serine 424 phospho-mimic and phospho-null mutants bidirectionally modulate long-term memory formation and synaptic plasticity in the adult and aging mouse brain.

Long-term memory formation is negatively regulated by histone deacetylase 3 (HDAC3), a transcriptional repressor. Emerging evidence suggests that post-translational phosphorylation of HDAC3 at its serine 424 (S424) residue is critical for its deacetylase activity in transcription. However, it remains unknown if HDAC3 S424 phosphorylation regulates the ability of HDAC3 to modulate long-term memory formation. To examine the functionality of S424, we expressed an HDAC3-S424D phospho-mimic mutant (constitutively active form) or an HDAC3-S424A phospho-null mutant (deacetylase dead form) in the dorsal hippocampus of mice. We assessed the functional consequence of these mutants on long-term memory (LTM) formation and long-term potentiation (LTP) in young adult male mice. We also assessed whether the HDAC3-S424A mutant could ameliorate age-related deficits in LTM and LTP in aging male and female mice. Results demonstrate that young adult male mice expressing the HDAC3-S424D phospho-mimic mutant in dorsal hippocampus exhibit significantly impaired LTM and LTP. In contrast, the HDAC3-S424A phospho-null mutant expressed in the hippocampus of young adult male mice enabled the transformation of subthreshold learning into robust LTM and enhanced LTP. Similarly, expression of the HDAC3-S424A mutant enabled LTM formation and enhanced LTP in aging male and aging female mice. Overall, these findings demonstrate that HDAC3 S424 is a pivotal residue that has the ability to bidirectionally regulate synaptic plasticity and LTM formation in the adult and aging brain.Significance statement Histone deacetylase 3 (HDAC3) is a negative regulator of synaptic plasticity and memory. However, the mechanism that regulates HDAC3 activity remains poorly understood. This study demonstrates the pivotal nature of Serine 424 of HDAC3 to bidirectionally regulate long-term potentiation, a form of synaptic plasticity, and long-term memory formation. Serine 424 is a phosphorylation site, suggesting that phosphorylation of HDAC3 is a key regulatory mechanism controlling its regulation of gene expression required for long-term memory. Indeed, expression of a Serine 424 phospho-null in the aging brain ameliorated age-dependent long-term synaptic plasticity and long-term memory deficits in aging male and aging female mice. Thus, this study provides new insight into the regulation of HDAC3 activity involved in cognitive processes.