Aberrant histone deacetylase2-mediated histone modifications and synaptic plasticity in the amygdala predisposes to anxiety and alcoholism

Biol Psychiatry. 2013 Apr 15;73(8):763-73. doi: 10.1016/j.biopsych.2013.01.012. Epub 2013 Feb 26.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetylation / drug effects
  • Alcohol Drinking / genetics
  • Alcoholism / enzymology*
  • Alcoholism / physiopathology
  • Amygdala / drug effects
  • Amygdala / metabolism*
  • Animals
  • Anxiety / enzymology*
  • Anxiety / physiopathology
  • Brain-Derived Neurotrophic Factor / metabolism
  • Cytoskeletal Proteins / metabolism
  • Dendritic Spines / ultrastructure
  • Epigenesis, Genetic / drug effects
  • Epigenesis, Genetic / genetics*
  • Epigenesis, Genetic / physiology
  • Ethanol / pharmacology
  • Gene Knockdown Techniques
  • Genetic Predisposition to Disease / genetics
  • Histone Deacetylase 2 / metabolism*
  • Histones / metabolism*
  • Isoenzymes / metabolism
  • Male
  • Microinjections
  • Neuronal Plasticity / drug effects
  • Neuronal Plasticity / genetics
  • Neuronal Plasticity / physiology*
  • RNA, Small Interfering / administration & dosage
  • RNA, Small Interfering / pharmacology
  • Rats


  • Brain-Derived Neurotrophic Factor
  • Cytoskeletal Proteins
  • Histones
  • Isoenzymes
  • RNA, Small Interfering
  • Ethanol
  • Histone Deacetylase 2