Histone modifications around individual BDNF gene promoters in prefrontal cortex are associated with extinction of conditioned fear.
Extinction of conditioned fear is an important model both of inhibitory learning and of behavior therapy for human anxiety disorders. Like other forms of learning, extinction learning is long-lasting and depends on regulated gene expression. Epigenetic mechanisms make an important contribution to persistent changes in gene expression; therefore, in these studies, we have investigated whether epigenetic regulation of gene expression contributes to fear extinction. Since brain-derived neurotrophic factor (BDNF) is crucial for synaptic plasticity and for the maintenance of long-term memory, we examined histone modifications around two BDNF gene promoters after extinction of cued fear, as potential targets of learning-induced epigenetic regulation of gene expression. Valproic acid (VPA), used for some time as an anticonvulsant and a mood stabilizer, modulates the expression of BDNF, and is a histone deacetylase (HDAC) inhibitor. Here, we report that extinction of conditioned fear is accompanied by a significant increase in histone H4 acetylation around the BDNF P4 gene promoter and increases in BDNF exon I and IV mRNA expression in prefrontal cortex, that VPA enhances long-term memory for extinction because of its HDAC inhibitor effects, and that VPA potentiates the effect of weak extinction training on histone H4 acetylation around both the BDNF P1 and P4 gene promoters and on BDNF exon IV mRNA expression. These results suggest a relationship between histone H4 modification, epigenetic regulation of BDNF gene expression, and long-term memory for extinction of conditioned fear. In addition, they suggest that HDAC inhibitors may become a useful pharmacological adjunct to psychotherapy for human anxiety disorders.
Bredy
Timothy W
TW
Department of Psychiatry and Biobehavioral Sciences, Brain Research Institute, Semel Institute for Neuroscience and Human Behavior, Los Angeles, California 90095, USA.
Wu
Hao
H
Crego
Cortney
C
Zellhoefer
Jessica
J
Sun
Yi E
YE
Barad
Mark
M
D000107:Acetylation; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D003213:Conditioning, Psychological; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005108:Extinction, Psychological / Q000502:physiology*; D005239:Fear; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D017397:Prefrontal Cortex / Q000378:metabolism / Q000502:physiology*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014635:Valproic Acid / Q000494:pharmacology
D019208:Brain-Derived Neurotrophic Factor; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D012333:RNA, Messenger; D014635:Valproic Acid