Vorinostat, a histone deacetylase inhibitor, facilitates fear extinction and enhances expression of the hippocampal NR2B-containing NMDA receptor gene

Department of Psychiatry and Neurosciences, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, 734-8551 Hiroshima, Japan.
Journal of Psychiatric Research (Impact Factor: 3.96). 02/2012; 46(5):635-43. DOI: 10.1016/j.jpsychires.2012.01.026
Source: PubMed


Histone acetylation, which alters the compact chromatin structure and changes the accessibility of DNA to regulatory proteins, is emerging as a fundamental mechanism for regulating gene expression. Histone deacetylase (HDAC) inhibitors increase histone acetylation and enhance fear extinction. In this study, we examined whether vorinostat, an HDAC inhibitor, facilitates fear extinction, using a contextual fear conditioning (FC) paradigm, in Sprague-Dawley rats. We found that vorinostat facilitated fear extinction. Next, the levels of global acetylated histone H3 and H4 were measured by Western blotting. We also assessed the effect of vorinostat on the hippocampal levels of NMDA receptor mRNA by real-time quantitative PCR (RT-PCR) and protein by Western blotting. 2 h after vorinostat administration, the levels acetylated histones and NR2B mRNA, but not NR1 or NR2A mRNA, were elevated in the hippocampus. The NR2B protein level was elevated 4 h after vorinostat administration. Last, we investigated the levels of acetylated histones and phospho-CREB (p-CREB) binding at the promoter of the NR2B gene using the chromatin immunoprecipitation (ChIP) assay followed by RT-PCR. The ChIP assay revealed increases in the levels of acetylated histones and they were accompanied by enhanced binding of p-CREB to its binding site at the promoter of the NR2B gene 2 h after vorinostat administration. These findings suggest that vorinostat increases the expression of NR2B in the hippocampus by enhancing histone acetylation, and this process may be implicated in fear extinction.

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    • "In line with such observations i.p. injection of sodium butyrate and intrahippocampal injections of trichostatin A facilitates fear extinction in mice (Lattal et al., 2007). Moreover, administration of SAHA facilitates fear extinction in naive rats (Fujita et al., 2012) and also in rats that had been exposed to the single prolonged stress paradigm, a model for PTSD (Ponomarev et al., 2010; Matsumoto et al., 2013). In contrast to the commonly used C57BL6J mouse it was demonstrated that 129S1/SvlmJ mice are unable to extinct fear memories. "
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    ABSTRACT: The orchestration of gene-expression programs is essential for cellular homeostasis. Epigenetic processes provide to the cell a key mechanism that allows the regulation of gene-expression networks in response to environmental stimuli. Recently epigenetic mechanisms such as histone-modifications have been implicated with cognitive function and altered epigenome plasticity has been linked to the pathogenesis of neurodegenerative and neuropsychiatric diseases. Thus, key regulators of epigenetic gene-expression have emerged as novel drug targets for brain diseases. Numerous recent review articles discuss in detail the current findings of epigenetic processes in brain diseases. The aim of this article is not to give yet another comprehensive overview of the field but to specifically address the question why the same epigenetic therapies that target histone-acetylation may be suitable to treat seemingly different diseases such as Alzheimer's disease and post-traumatic stress disorder.
    Frontiers in Neuroscience 06/2014; 8(8):160. DOI:10.3389/fnins.2014.00160 · 3.66 Impact Factor
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    • "Given that HDAC inhibitors have been widely reported to enhance memory, recent work has turned toward examining the potential for HDAC inhibition to enhance extinction memory as it may have clinical implications. A few labs have now provided evidence for the benefit of HDAC inhibition on fear extinction learning by demonstrating that systemic HDAC inhibition is capable of facilitating extinction for auditory fear memory (Lattal et al., 2007; Bredy and Barad, 2008; Fujita et al., 2012; Itzhak et al., 2012) (Figure 2) and facilitating extinction of cocaine conditioned place preference (Malvaez et al., 2010). "
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    ABSTRACT: This review examines recent work on epigenetic mechanisms underlying animal models of fear learning as well as its translational implications in disorders of fear regulation, such as Post-traumatic Stress Disorder (PTSD). Specifically, we will examine work outlining roles of differential histone acetylation and DNA-methylation associated with consolidation, reconsolidation, and extinction in Pavlovian fear paradigms. We then focus on the numerous studies examining the epigenetic modifications of the Brain-derived neurotrophin factor (BDNF) pathway and the extension of these findings from animal models to recent work in human clinical populations. We will also review recently published data on FKBP5 regulation of glucocorticoid receptor function, and how this is modulated in animal models of PTSD and in human clinical populations via epigenetic mechanisms. As glucocorticoid regulation of memory consolidation is well established in fear models, we examine how these recent data contribute to our broader understanding of fear memory formation. The combined recent progress in epigenetic modulation of memory with the advances in fear neurobiology suggest that this area may be critical to progress in our understanding of fear-related disorders with implications for new approaches to treatment and prevention.
    Frontiers in Psychiatry 07/2013; 4:62. DOI:10.3389/fpsyt.2013.00062
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    • "The non-selective HDAC inhibitor valproic acid can facilitate not only the acquisition and extinction of conditioned fear, but also the reconsolidation of this memory (Bredy and Barad, 2008). Similar results have been obtained with the HDAC inhibitor vorinostat (Fujita et al., 2012). It has also been shown that deficits in the extinction learning of conditioned fear in isogenic 129S1 (S1) mice can be recovered by administration of an HDAC inhibitor (Whittle et al., 2013). "
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    ABSTRACT: Theories of drug addiction that incorporate various concepts from the fields of learning and memory have led to the idea that classical and operant conditioning principles underlie the compulsiveness of addictive behaviors. Relapse often results from exposure to drug-associated cues, and the ability to extinguish these conditioned behaviors through inhibitory learning could serve as a potential therapeutic approach for those who suffer from addiction. This review will examine the evidence that extinction learning alters neuronal plasticity in specific brain regions and pathways. In particular, subregions of the prefrontal cortex (PFC) and their projections to other brain regions have been shown to differentially modulate drug-seeking and extinction behavior. Additionally, there is a growing body of research demonstrating that manipulation of neuronal plasticity can alter extinction learning. Therefore, the ability to alter plasticity within areas of the PFC through pharmacological manipulation could facilitate the acquisition of extinction and provide a novel intervention to aid in the extinction of drug-related memories.
    Frontiers in Psychiatry 05/2013; 4(46):46. DOI:10.3389/fpsyt.2013.00046
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