Reassessing the effects of histone deacetylase inhibitors on hippocampal memory and cognitive aging

Hippocampus. 2014 Aug;24(8):1006-16. doi: 10.1002/hipo.22286. Epub 2014 Apr 30.


Converging results link histone acetylation dynamics to hippocampus-dependent memory, including evidence that histone deacetylase inhibitor (HDACi) administration enhances long-term memory. Previously, we demonstrated that aging disrupts the coordinated epigenetic response to recent experience observed in the young adult hippocampus. Here, we extended that work to test the cognitive effects of a novel, brain-penetrant HDACi (EVX001688; EVX) that we confirmed yields robust, relatively long lasting dose-dependent increases in histone acetylation in the hippocampus. In young rats, acute systemic EVX administration, scheduled to yield elevated histone acetylation levels during training in a contextual fear conditioning (CFC) task, had no effect on memory retention at 24 h at any dose examined (10, 30, or 60 mg/kg). Pretraining injection of another HDACi, sodium butyrate, also failed to affect fear memory, and CFC training itself had no influence on hippocampal histone acetylation at 1 hour in mice or two strains of rats. EVX administration before water maze training in young rats yielded a modest effect such that the middle dose produced marginally better 24-h retention than either the low or high dose, but only a small numerical benefit relative to vehicle. Guided by those findings, a final experiment tested the influence of pretraining EVX treatment on age-related spatial memory impairment. The results, revealing no effect on performance, are consistent with the idea that effective procognitive HDACi treatments in aging may require intervention aimed at restoring coordinated epigenetic regulation rather than bulk increases in hippocampal histone acetylation.

Keywords: aging; epigenetics; hippocampus; histone deacetylase inhibitor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Acetylation / drug effects
  • Aging / drug effects*
  • Aging / physiology
  • Animals
  • Butyric Acid / pharmacology
  • Cognition / drug effects*
  • Cognition / physiology
  • Conditioning, Psychological / drug effects
  • Conditioning, Psychological / physiology
  • Dose-Response Relationship, Drug
  • Fear / drug effects
  • Fear / physiology
  • Hippocampus / drug effects*
  • Hippocampus / growth & development
  • Hippocampus / physiology
  • Histone Deacetylase Inhibitors / pharmacology*
  • Histones / metabolism
  • Male
  • Maze Learning / drug effects
  • Maze Learning / physiology
  • Memory / drug effects*
  • Memory / physiology
  • Mice, Inbred C57BL
  • Rats, Long-Evans
  • Rats, Sprague-Dawley
  • Spatial Memory / drug effects
  • Spatial Memory / physiology


  • Histone Deacetylase Inhibitors
  • Histones
  • Butyric Acid