This study investigates the role of histone deacetylase 2 (HDAC2) in memory formation and synaptic plasticity. The authors found that neuron-specific overexpression of HDAC2 reduced dendritic spine density, synapse number, synaptic plasticity, and memory formation, while HDAC2 deficiency increased these parameters. Conversely, chronic HDAC inhibitor (HDACi) treatment, similar to HDAC2 deficiency, facilitated memory formation. HDAC2 was associated with promoters of genes involved in synaptic plasticity and memory formation, suggesting that it negatively regulates these processes. Additionally, HDAC2 was found to associate with the co-repressor complex CoREST, which may contribute to its role in memory regulation. The study concludes that HDAC2 is a key regulator of synaptic plasticity and memory formation, and its selective inhibition could be a therapeutic approach for memory impairment in human diseases.This study investigates the role of histone deacetylase 2 (HDAC2) in memory formation and synaptic plasticity. The authors found that neuron-specific overexpression of HDAC2 reduced dendritic spine density, synapse number, synaptic plasticity, and memory formation, while HDAC2 deficiency increased these parameters. Conversely, chronic HDAC inhibitor (HDACi) treatment, similar to HDAC2 deficiency, facilitated memory formation. HDAC2 was associated with promoters of genes involved in synaptic plasticity and memory formation, suggesting that it negatively regulates these processes. Additionally, HDAC2 was found to associate with the co-repressor complex CoREST, which may contribute to its role in memory regulation. The study concludes that HDAC2 is a key regulator of synaptic plasticity and memory formation, and its selective inhibition could be a therapeutic approach for memory impairment in human diseases.