Targeting acetyl-CoA metabolism attenuates the formation of fear memories through reduced activity-dependent histone acetylation

Histone acetylation is a key component in the consolidation of long-term fear memories, which are models for highly resilient and durable memory. Histone acetylation is fueled by acetyl-CoA and recently, nuclear-localized metabolic enzymes that produce this metabolite have emerged as direct and local regulators of histone acetylation. In particular, Acetyl-coA synthetase 2 (ACSS2) mediates histone acetylation in the mouse hippocampus. However, whether ACSS2 regulates long-term fear memory remains to be determined. Here, we show that Acss2 knockout is well-tolerated in mice, yet the Acss2 null mouse exhibits reduced acquisition of long-term fear memory. Loss of Acss2 leads to reductions in both histone acetylation and expression of critical learning and memory-related genes in the dorsal hippocampus, specifically following fear conditioning. Further, systemic administration of blood-brain-barrier (BBB)-permeable Acss2 inhibitors during the consolidation window reduces fear memory formation in mice and rats, and reduces anxiety in a predator-scent-stress (PSS) paradigm. Our findings suggest that nuclear acetyl-CoA metabolism via ACSS2 plays a critical, previously unappreciated role in the formation of fear memories. Overall design: Included are two separately analyzed experiments that used RNA-seq to examine the transcriptome in the hippocampus from mice on a C57BL6/J background harboring a deletion of the metabolic gene Acss2. Experiment 1 (6 samples) consists of whole hippocampi processed from 3 genotypes (Acss2 WT[reference], Acss2 Het, and Acss2 KO), with two replicates each. All samples were processed together. Experiment 2 (17 samples) consists of 2 genotypes (Acss2 WT, Acss2 KO), 2 conditions (homecage-housed[reference], and fear conditioned). Replicates included are: 5 replicates WT untreated, 3 replicates WT fear conditioned, 5 replicates ACSS2- untreated, 4 replicates ACSS2- fear conditioned.