PMID- 23485013 OWN - NLM STAT- MEDLINE DCOM- 20140901 LR - 20220309 IS - 1873-2402 (Electronic) IS - 0006-3223 (Print) IS - 0006-3223 (Linking) VI - 73 IP - 8 DP - 2013 Apr 15 TI - Aberrant histone deacetylase2-mediated histone modifications and synaptic plasticity in the amygdala predisposes to anxiety and alcoholism. PG - 763-73 LID - S0006-3223(13)00052-8 [pii] LID - 10.1016/j.biopsych.2013.01.012 [doi] AB - BACKGROUND: Epigenetic mechanisms have been implicated in psychiatric disorders, including alcohol dependence. However, the epigenetic basis and role of specific histone deacetylase (HDAC) isoforms in the genetic predisposition to anxiety and alcoholism is unknown. METHODS: We measured amygdaloid HDAC activity, levels of HDAC isoforms, and histone H3 acetylation in selectively bred alcohol-preferring (P) and -nonpreferring (NP) rats. We employed HDAC2 small interfering RNA infusion into the central nucleus of amygdala (CeA) of P rats to determine the causal role of HDAC2 in anxiety-like and alcohol-drinking behaviors. Chromatin immunoprecipitation analysis was performed to examine the histone acetylation status of brain-derived neurotrophic factor (Bdnf) and activity-regulated cytoskeleton associated protein (Arc) genes. Golgi-Cox staining was performed to measure dendritic spine density. RESULTS: We found that P rats innately display higher nuclear HDAC activity and HDAC2 but not HDAC 1, 3, 4, 5, and 6 protein levels and lower acetylation of H3-K9 but not H3-K14, in the CeA and medial nucleus of amygdala compared with NP rats. Acute ethanol exposure decreased amygdaloid HDAC activity and HDAC2 protein levels, increased global and gene (Bdnf and Arc)-specific histone acetylation, and attenuated anxiety-like behaviors in P rats but had no effects in NP rats. The HDAC2 knockdown in the CeA attenuated anxiety-like behaviors and voluntary alcohol but not sucrose consumption in P rats and increased histone acetylation of Bdnf and Arc with a resultant increase in protein levels that correlated with increased dendritic spine density. CONCLUSIONS: These novel data demonstrate the role of HDAC2-mediated epigenetic mechanisms in anxiety and alcoholism. CI - Published by Elsevier Inc. FAU - Moonat, Sachin AU - Moonat S AD - Department of Psychiatry, University of Illinois at Chicago, IL 60612, USA. FAU - Sakharkar, Amul J AU - Sakharkar AJ FAU - Zhang, Huaibo AU - Zhang H FAU - Tang, Lei AU - Tang L FAU - Pandey, Subhash C AU - Pandey SC LA - eng GR - R29 AA010005/AA/NIAAA NIH HHS/United States GR - U01 AA019971/AA/NIAAA NIH HHS/United States GR - AA-019971/AA/NIAAA NIH HHS/United States GR - R24 AA015512/AA/NIAAA NIH HHS/United States GR - AA-016690/AA/NIAAA NIH HHS/United States GR - R01 AA010005/AA/NIAAA NIH HHS/United States GR - R01 AA016690/AA/NIAAA NIH HHS/United States GR - R24AA-015512/AA/NIAAA NIH HHS/United States GR - R01 AA013341/AA/NIAAA NIH HHS/United States GR - AA-013341/AA/NIAAA NIH HHS/United States GR - AA-010005/AA/NIAAA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20130226 PL - United States TA - Biol Psychiatry JT - Biological psychiatry JID - 0213264 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Cytoskeletal Proteins) RN - 0 (Histones) RN - 0 (Isoenzymes) RN - 0 (RNA, Small Interfering) RN - 3K9958V90M (Ethanol) RN - EC 3.5.1.98 (Histone Deacetylase 2) SB - IM MH - Acetylation/drug effects MH - Alcohol Drinking/genetics MH - Alcoholism/*enzymology/physiopathology MH - Amygdala/drug effects/*metabolism MH - Animals MH - Anxiety/*enzymology/physiopathology MH - Brain-Derived Neurotrophic Factor/metabolism MH - Cytoskeletal Proteins/metabolism MH - Dendritic Spines/ultrastructure MH - Epigenesis, Genetic/drug effects/*genetics/physiology MH - Ethanol/pharmacology MH - Gene Knockdown Techniques MH - Genetic Predisposition to Disease/genetics MH - Histone Deacetylase 2/*metabolism MH - Histones/*metabolism MH - Isoenzymes/metabolism MH - Male MH - Microinjections MH - Neuronal Plasticity/drug effects/genetics/*physiology MH - RNA, Small Interfering/administration & dosage/pharmacology MH - Rats PMC - PMC3718567 MID - NIHMS450107 EDAT- 2013/03/15 06:00 MHDA- 2014/09/02 06:00 PMCR- 2014/04/15 CRDT- 2013/03/15 06:00 PHST- 2012/05/15 00:00 [received] PHST- 2013/01/04 00:00 [revised] PHST- 2013/01/04 00:00 [accepted] PHST- 2013/03/15 06:00 [entrez] PHST- 2013/03/15 06:00 [pubmed] PHST- 2014/09/02 06:00 [medline] PHST- 2014/04/15 00:00 [pmc-release] AID - S0006-3223(13)00052-8 [pii] AID - 10.1016/j.biopsych.2013.01.012 [doi] PST - ppublish SO - Biol Psychiatry. 2013 Apr 15;73(8):763-73. doi: 10.1016/j.biopsych.2013.01.012. Epub 2013 Feb 26.