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.Substantial evidence indicates that extinction of conditioned fear, the reduction in responding to a feared cue when the cue is repeatedly presented without any adverse consequence, is new learning that inhibits the expression of a conditioned association rather than erasing it. For example, conditioned fear shows "spontaneous recovery" after the passage of time (Baum 1988), "reinstatement" after presentations of the unconditioned stimulus (US) alone (Rescorla and Heth 1975), and "renewal" when the feared cue is presented in a context different from that of extinction training (Bouton and King 1983). Efforts to understand the mechanisms of this form of learning have increased recently, particularly since it is an important model of anxiety disorder treatment.Many forms of learning, including extinction, are dependent on changes in gene expression ( . Dynamic changes in chromatin structure make an important contribution to the regulation of tissue-specific gene expression. In particular, histone acetylation/deacetylation and dimethylation of specific lysine residues on nucleosomal histone proteins (i.e., H3-K9) and DNA methylation of CpG dinucleotides within promoter regions are ways that chromatin remodeling can influence ongoing transcription and synaptic plasticity (Martinowich et al. 2003;Levenson et al. 2...

Recent advances have revealed a plethora of genes, signalling pathways, cellular and circuit processes involved in learning and memory. Convergent evidence demonstrates that molecular mechanisms that regulate long‐lasting changes in synaptic function are critical for learning and memory. This evidence has had a key role in unraveling mechanisms responsible for learning disabilities. For example, mutations in the neurofibromatosis type I ( NF1 ) gene are a common genetic cause for learning disabilities. Studies in mice revealed that these learning deficits are caused by increases in Ras signalling leading to enhancements in synaptic inhibition and synaptic plasticity deficits. These deficits can be reversed by manipulations that target Ras signalling or inhibition. Current clinical trials are testing the efficacy of these treatments in NF1 . Studies in other genetic causes for learning disabilities have shown that it is possible to develop mechanism‐based treatments for these disorders in mice that are effective even when they are started in adulthood. Key Concepts: The molecular mechanisms that regulate long‐lasting changes in synaptic function are critical for learning and memory. Our growing understanding of mechanisms of memory has been effectively used to unravel the causes for memory deficits associated with animal models of several key genetic disorders, including NF1, tuberous sclerosis and fragile X. It is possible to develop mechanism‐based treatments for developmental disorders that are effective even when treatment is started in adulthood.