The neuronal encoding of long-term memories relies on the rapid, coordinated transcription of activity-dependent genes. This process is tightly controlled by several mechanisms, including histone acetylation, which is fueled in part by nuclear acetyl-CoA pools produced by acetyl-CoA synthetase 2 (ACSS2). Loss of ACSS2 negatively impacts spatial memory formation in the dorsal hippocampus, but the extent to which ACSS2 other memory paradigms, including models of post-traumatic stress disorder (PTSD) and Alzheimer’s disease (AD), is unclear. Here, we used a constitutive Acss2KO mouse model to determine how ACSS2 contributes to histone acetylation and activity-related transcription during the formation of long-term fear memories, which model aspects of PTSD. We found that loss of ACSS2 led to deficits in cued and contextual fear recall, which were underpinned by reductions in histone acetylation and activity-related gene expression. Administration of a small-molecule ACSS2 inhibitor during memory acquisition similarly reduced fear memory in mice and rats. Loss of ACSS2 also exacerbated memory and transcriptional deficits in a mouse AD model involving injection of pathological Tau aggregates directly into the brain. Conversely, dietary supplementation with acetate, ACSS2’s substrate, ameliorated both behavioral and transcriptional deficits associated with AD-Tau. This thesis also presents preliminary data suggesting that ACSS2 plays a similar role in astrocytes – regulating the expression of a subset of immediate early genes induced by fear conditioning. Finally, we leveraged mass spectrometry-based techniques to map the interactome of ACSS2 in mouse hippocampus and a neuronal cell model. We found that ACSS2 associated with a number of chromatin-associated proteins involved in histone deacetylation and transcriptional repression, pointing to a potential role for ACSS2 in the dynamic cycles of histone acetylation and deacetylation at the promoters of rapidly induced genes, such as the activity-dependent genes involved in the encoding of long-term memories. Taken together, our results provide evidence of ACSS2’s role in neurons and astrocytes, and in clinically relevant memory-related disorders, like PTSD and AD.