Sodium Butyrate Abolishes Lipopolysaccharide-Induced Depression-Like Behaviors and Hippocampal Microglial Activation in Mice

Brain Res. 2018 Feb 1;1680:13-38. doi: 10.1016/j.brainres.2017.12.004. Epub 2017 Dec 8.


Patients with major depressive disorder have elevated peripheral inflammation; the degree of this increase correlates with the severity of the disorder. Chronic psychological stress increases pro-inflammatory cytokines and promotes microglial activation, leading to stress vulnerability. Epigenetics, including DNA methylation and histone modification, are also related to the pathophysiology of major depressive disorder. Sodium butyrate (SB), a histone deacetylase inhibitor, exerts an antidepressant effect by altering gene expression in the hippocampus. In this study, we investigated whether lipopolysaccharide (LPS)-induced depressive-like behaviors in mice are affected by the repeated treatment with SB. Intraperitoneal injection of LPS (5 mg/kg) induced cytokines and ionized calcium-binding adaptor molecule 1(Iba1), a marker of microglial activation, in the hippocampus. It also increased the immobility time in a forced swim test, without changing locomotion. Repeated treatment with SB reduced LPS-induced alterations. These findings suggested that epigenetic regulation exist in hippocampal microglial activation, and is involved in depressive-like behaviors associated with neuro-inflammation. Further, using cDNA microarray analyses, we examined whether LPS and SB treatment affected the microglial gene profiles. Our results indicated 64 overlapping genes, between LPS-increased genes and SB-decreased genes. Among these genes, EF hand calcium binding domain 1 was a particularly distinct candidate gene. Altogether, our findings indicated that microglial activation mediated through epigenetic regulation may be involved in depressive-like behaviors. In addition, we demonstrated the effect of SB on gene information in hippocampal microglia under neuroinflammatory conditions.

Keywords: Epigenetics; Hippocampus; Histone deacetylase inhibitor; Inflammation; Microglia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology
  • Antidepressive Agents / therapeutic use
  • Butyric Acid / pharmacology*
  • Butyric Acid / therapeutic use*
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism
  • Cytokines / genetics
  • Cytokines / metabolism*
  • Depression / chemically induced
  • Depression / drug therapy*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Exploratory Behavior / drug effects
  • Gene Expression / drug effects
  • Hippocampus / cytology*
  • Histones / genetics
  • Histones / metabolism
  • Lipopolysaccharides / toxicity
  • Mice
  • Mice, Inbred C57BL
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism
  • Microglia / drug effects*
  • Oligonucleotide Array Sequence Analysis
  • RNA, Messenger / metabolism
  • Swimming / psychology


  • Aif1 protein, mouse
  • Antidepressive Agents
  • Calcium-Binding Proteins
  • Cytokines
  • Histones
  • Lipopolysaccharides
  • Microfilament Proteins
  • RNA, Messenger
  • Butyric Acid