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

Abstract

Histone acetylation is a key component in the consolidation of long-term fear memories. Epigenetic enzymes involved in histone acetylation, including histone acetyltransferases and deacetylases, have been put forward as potential pharmacological targets in the treatment of pathological fear memories, such as those that underlie post-traumatic stress disorder (PTSD). However, these enzymes typically play a ubiquitous role in gene regulation, which precludes the clinical use of systemic manipulations. Recently, we have found that a nuclear-localized metabolic enzyme, Acetyl-coA synthetase 2 (Acss2), modulates histone acetylation during learning and memory. Loss of Acss2 is well-tolerated in mice, with no impact on general health or baseline behavior. Here, we show that an Acss2 null mouse model shows reduced acquisition of long-term fear memories in assays of contextual and cued fear conditioning. We find that loss of Acss2 leads to consolidation-specific reductions in both histone acetylation and the expression of critical learning and memory-related genes in the dorsal hippocampus. Further, we show that systemic administration of blood-brain-barrier (BBB)-permeable Acss2 inhibitors during the consolidation window reduces fear memory formation in mice and rats, and also reduces anxiety in a predator-scent-stress (PSS) paradigm. Our findings suggest that Acss2 plays a critical role in the formation of fear memories, and represents a potential pharmacological target in the treatment of PTSD.

ACSS2 upregulation enhances neuronal resilience to aging and tau-associated neurodegeneration

“…1B). In accordance with the established role of ACSS2 to promote histone acetylation (16)(17)(18), we observed increased levels of transcription-linked H3K9ac and H3K27ac in neurons transduced with AAV.ACSS2 compared to vector control (Fig. 1, C to F).…”

“…In neurons, histone acetylation can be heavily dependent on the activity of ACSS2 (16). We have shown that ACSS2 resides on chromatin generating acetyl-CoA to supply key histone acetyltransferases (HATs) (16,17), allowing rapid upregulation of critical neuronal genes central to learning and memory (16,18). ACSS2 knockout leads to animals defective in memory; upregulation of ACSS2 has effects to boost some synaptic genes in an amyloid-beta expressing mouse (19).…”