The regulation of histone acetylation during memory formation in the hippocampus is crucial for long-term memory. This study investigated how histone acetylation, specifically of histone H3, is regulated during the early stages of long-term memory formation in the hippocampus, particularly in the CA1 region, using a contextual fear conditioning paradigm. The results showed that contextual fear conditioning increased histone H3 acetylation, an effect dependent on NMDA receptor and ERK activation, and was blocked by a latent inhibition paradigm. Activation of NMDA receptors in CA1 in vitro increased histone H3 acetylation, which was blocked by ERK inhibition. Additionally, activation of ERK through the protein kinase C or protein kinase A pathways also increased histone H3 acetylation. Elevating histone acetylation using histone deacetylase inhibitors like trichostatin A or sodium butyrate enhanced long-term potentiation (LTP) in the CA1 region, a candidate mechanism for long-term memory formation. In vivo, sodium butyrate injection prior to contextual fear conditioning enhanced long-term memory formation. These findings suggest that changes in histone acetylation and chromatin structure are involved in long-term memory formation. The study also showed that histone acetylation is regulated by NMDA receptors and ERK signaling pathways, and that histone acetylation is specific to associative memory formation. The results indicate that histone acetylation is a key mechanism in the regulation of gene expression and long-term memory formation. The study also demonstrated that histone deacetylase inhibitors like TSA and sodium butyrate enhance LTP induction, which is dependent on transcription. These findings suggest that histone acetylation is a critical factor in the regulation of synaptic plasticity and long-term memory formation.The regulation of histone acetylation during memory formation in the hippocampus is crucial for long-term memory. This study investigated how histone acetylation, specifically of histone H3, is regulated during the early stages of long-term memory formation in the hippocampus, particularly in the CA1 region, using a contextual fear conditioning paradigm. The results showed that contextual fear conditioning increased histone H3 acetylation, an effect dependent on NMDA receptor and ERK activation, and was blocked by a latent inhibition paradigm. Activation of NMDA receptors in CA1 in vitro increased histone H3 acetylation, which was blocked by ERK inhibition. Additionally, activation of ERK through the protein kinase C or protein kinase A pathways also increased histone H3 acetylation. Elevating histone acetylation using histone deacetylase inhibitors like trichostatin A or sodium butyrate enhanced long-term potentiation (LTP) in the CA1 region, a candidate mechanism for long-term memory formation. In vivo, sodium butyrate injection prior to contextual fear conditioning enhanced long-term memory formation. These findings suggest that changes in histone acetylation and chromatin structure are involved in long-term memory formation. The study also showed that histone acetylation is regulated by NMDA receptors and ERK signaling pathways, and that histone acetylation is specific to associative memory formation. The results indicate that histone acetylation is a key mechanism in the regulation of gene expression and long-term memory formation. The study also demonstrated that histone deacetylase inhibitors like TSA and sodium butyrate enhance LTP induction, which is dependent on transcription. These findings suggest that histone acetylation is a critical factor in the regulation of synaptic plasticity and long-term memory formation.