title: Vorinostat, a histone deacetylase inhibitor, facilitates fear extinction and enhances expression of the hippocampal NR2B-containing NMDA receptor gene.
abstract: 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.
authors.affiliation: 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.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Fujita
authors.forename: Shigeru
authors.initials: S
authors.lastname: Morinobu
authors.forename: Shiro
authors.initials: S
authors.lastname: Takei
authors.forename: Manabu
authors.initials: M
authors.lastname: Fuchikami
authors.forename: Tomoya
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Shigeto
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Shigeto
authors.initials: S
authors.lastname: Yamawaki
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D050882:CREB-Binding Protein / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D005106:Exploratory Behavior / Q000187:drug effects; D005108:Extinction, Psychological / Q000187:drug effects*; D005239:Fear / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006657:Histones / Q000378:metabolism; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D014828:Vocalization, Animal / Q000187:drug effects; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; C121001:NR2B NMDA receptor; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D000077337:Vorinostat; D050882:CREB-Binding Protein