HDAC2 negatively regulates memory formation and synaptic plasticity. The study shows that overexpression of HDAC2 in neurons reduces dendritic spine density, synapse number, synaptic plasticity, and memory formation, while its deficiency increases synapse number and memory facilitation, similar to chronic HDACi treatment. HDAC2 deficiency leads to increased synaptic plasticity and memory, suggesting that HDAC2 negatively regulates learning and memory. HDAC2 is associated with the promoters of genes involved in synaptic plasticity and memory formation. Chromatin modifications, particularly histone acetylation, are involved in memory formation. HDAC inhibitors, such as SAHA, enhance memory formation by increasing histone acetylation. HDAC2, but not HDAC1, is involved in memory formation. HDAC2 overexpression impairs hippocampus-dependent memory formation and working memory, while HDAC2 deficiency enhances associative learning and spatial working memory. HDAC2 regulates synaptogenesis and synaptic plasticity by suppressing neuronal gene expression. HDAC2 is more abundantly expressed in neurons and associates with CoREST, a co-repressor, which is involved in repressing neuronal gene expression. HDAC2 is the major target of HDACi in eliciting memory enhancement. The study highlights the role of HDAC2 in modulating synaptic plasticity and learning and memory, suggesting that HDAC2-selective inhibitors could be developed for memory-related diseases.HDAC2 negatively regulates memory formation and synaptic plasticity. The study shows that overexpression of HDAC2 in neurons reduces dendritic spine density, synapse number, synaptic plasticity, and memory formation, while its deficiency increases synapse number and memory facilitation, similar to chronic HDACi treatment. HDAC2 deficiency leads to increased synaptic plasticity and memory, suggesting that HDAC2 negatively regulates learning and memory. HDAC2 is associated with the promoters of genes involved in synaptic plasticity and memory formation. Chromatin modifications, particularly histone acetylation, are involved in memory formation. HDAC inhibitors, such as SAHA, enhance memory formation by increasing histone acetylation. HDAC2, but not HDAC1, is involved in memory formation. HDAC2 overexpression impairs hippocampus-dependent memory formation and working memory, while HDAC2 deficiency enhances associative learning and spatial working memory. HDAC2 regulates synaptogenesis and synaptic plasticity by suppressing neuronal gene expression. HDAC2 is more abundantly expressed in neurons and associates with CoREST, a co-repressor, which is involved in repressing neuronal gene expression. HDAC2 is the major target of HDACi in eliciting memory enhancement. The study highlights the role of HDAC2 in modulating synaptic plasticity and learning and memory, suggesting that HDAC2-selective inhibitors could be developed for memory-related diseases.