title: Histone acetylation rescues contextual fear conditioning in nNOS KO mice and accelerates extinction of cued fear conditioning in wild type mice.
abstract: Epigenetic regulation of chromatin structure is an essential molecular mechanism that contributes to the formation of synaptic plasticity and long-term memory (LTM). An important regulatory process of chromatin structure is acetylation and deacetylation of histone proteins. Inhibition of histone deacetylase (HDAC) increases acetylation of histone proteins and facilitate learning and memory. Nitric oxide (NO) signaling pathway has a role in synaptic plasticity, LTM and regulation of histone acetylation. We have previously shown that NO signaling pathway is required for contextual fear conditioning. The present study investigated the effects of systemic administration of the HDAC inhibitor sodium butyrate (NaB) on fear conditioning in neuronal nitric oxide synthase (nNOS) knockout (KO) and wild type (WT) mice. The effect of single administration of NaB on total H3 and H4 histone acetylation in hippocampus and amygdala was also investigated. A single administration of NaB prior to fear conditioning (a) rescued contextual fear conditioning of nNOS KO mice and (b) had long-term (weeks) facilitatory effect on the extinction of cued fear memory of WT mice. The facilitatory effect of NaB on extinction of cued fear memory of WT mice was confirmed in a study whereupon NaB was administered during extinction. Results suggest that (a) the rescue of contextual fear conditioning in nNOS KO mice is associated with NaB-induced increase in H3 histone acetylation and (b) the accelerated extinction of cued fear memory in WT mice is associated with NaB-induced increase in H4 histone acetylation. Hence, a single administration of HDAC inhibitor may rescue NO-dependent cognitive deficits and afford a long-term accelerating effect on extinction of fear memory of WT mice.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL 33136, USA. yitzhak@med.miami.edu
authors.forename: Yossef
authors.initials: Y
authors.lastname: Itzhak
authors.forename: Karen L
authors.initials: KL
authors.lastname: Anderson
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Kelley
authors.forename: Martin
authors.initials: M
authors.lastname: Petkov
mesh_terms: D000107:Acetylation; D000679:Amygdala / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002087:Butyrates / Q000008:administration & dosage / Q000494:pharmacology; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D005108:Extinction, Psychological / Q000187:drug effects / Q000502:physiology; D005239:Fear / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000187:drug effects / Q000502:physiology*; D006657:Histones / Q000378:metabolism; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000502:physiology*; D052248:Nitric Oxide Synthase Type I / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D002087:Butyrates; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D009569:Nitric Oxide; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D006655:Histone Deacetylases