title: Antidepressant-like effect of sodium butyrate is associated with an increase in TET1 and in 5-hydroxymethylation levels in the Bdnf gene.
abstract: BACKGROUND
  Epigenetic drugs like sodium butyrate (NaB) show antidepressant-like effects in preclinical studies, but the exact molecular mechanisms of the antidepressant effects remain unknown. While research using NaB has mainly focused on its role as a histone deacetylase inhibitor (HDACi), there is also evidence that NaB affects DNA methylation.
  
  
  METHODS
  The purpose of this study was to examine NaB's putative antidepressant-like efficacy in relation to DNA methylation changes in the prefrontal cortex of an established genetic rat model of depression (the Flinders Sensitive Line [FSL]) and its controls (the Flinders Resistant Line).
  
  
  RESULTS
  The FSL rats had lower levels of ten-eleven translocation methylcytosine dioxygenase 1 (TET1), which catalyzes the conversion of DNA methylation to hydroxymethylation. As indicated by the behavioral despair test, chronic administration of NaB had antidepressant-like effects in the FSL and was accompanied by increased levels of TET1. The TET1 upregulation was also associated with an increase of hydroxymethylation and a decrease of methylation in brain-derived neurotrophic factor (Bdnf), a gene associated with neurogenesis and synaptic plasticity. These epigenetic changes were associated with a corresponding BDNF overexpression.
  
  
  CONCLUSIONS
  Our data support the antidepressant efficacy of HDACis and suggest that their epigenetic effects may also include DNA methylation changes that are mediated by demethylation-facilitating enzymes like TET1.
authors.affiliation: Department of Molecular Medicine and Surgery, Neurogenetics Unit, Karolinska Institutet, Stockholm, Sweden (Drs Wei, Melas, and Lavebratt); Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden (Drs Wei, Melas, and Lavebratt); Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark (Dr Wegener); Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa (Dr Wegener); and Department of Clinical Neuroscience, Section for Psychiatry, Karolinska Institutet, Stockholm, Sweden (Dr Mathé).
authors.forename: Yabin
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Department of Molecular Medicine and Surgery, Neurogenetics Unit, Karolinska Institutet, Stockholm, Sweden (Drs Wei, Melas, and Lavebratt); Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden (Drs Wei, Melas, and Lavebratt); Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark (Dr Wegener); Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa (Dr Wegener); and Department of Clinical Neuroscience, Section for Psychiatry, Karolinska Institutet, Stockholm, Sweden (Dr Mathé).
authors.forename: Philippe A
authors.initials: PA
authors.lastname: Melas
authors.affiliation: Department of Molecular Medicine and Surgery, Neurogenetics Unit, Karolinska Institutet, Stockholm, Sweden (Drs Wei, Melas, and Lavebratt); Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden (Drs Wei, Melas, and Lavebratt); Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark (Dr Wegener); Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa (Dr Wegener); and Department of Clinical Neuroscience, Section for Psychiatry, Karolinska Institutet, Stockholm, Sweden (Dr Mathé).
authors.forename: Gregers
authors.initials: G
authors.lastname: Wegener
authors.affiliation: Department of Molecular Medicine and Surgery, Neurogenetics Unit, Karolinska Institutet, Stockholm, Sweden (Drs Wei, Melas, and Lavebratt); Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden (Drs Wei, Melas, and Lavebratt); Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark (Dr Wegener); Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa (Dr Wegener); and Department of Clinical Neuroscience, Section for Psychiatry, Karolinska Institutet, Stockholm, Sweden (Dr Mathé).
authors.forename: Aleksander A
authors.initials: AA
authors.lastname: Mathé
authors.affiliation: Department of Molecular Medicine and Surgery, Neurogenetics Unit, Karolinska Institutet, Stockholm, Sweden (Drs Wei, Melas, and Lavebratt); Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden (Drs Wei, Melas, and Lavebratt); Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark (Dr Wegener); Centre of Excellence for Pharmaceutical Sciences, North-West University, Potchefstroom, South Africa (Dr Wegener); and Department of Clinical Neuroscience, Section for Psychiatry, Karolinska Institutet, Stockholm, Sweden (Dr Mathé).
authors.forename: Catharina
authors.initials: C
authors.lastname: Lavebratt
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D020148:Butyric Acid / Q000494:pharmacology*; D019175:DNA Methylation / Q000187:drug effects*; D003866:Depressive Disorder / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D049308:Dioxygenases / Q000378:metabolism*; D004195:Disease Models, Animal; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D008297:Male; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D056572:Histone Deacetylase Inhibitors; D020148:Butyric Acid; C000601821:TET1 protein, rat; D049308:Dioxygenases
keywords: DNA methylation; TET1; depression; epigenetics