Antidepressant-like effect of sodium butyrate (HDAC inhibitor) and its molecular mechanism of action in the rat hippocampus

Abstract

Objectives. Epigenetic mechanisms, such as changes in gene expression resulting from chromatin remodeling through histone acetylation, have been implicated in the pathophysiology of depression. However, the antidepressant-like effect of the histone deacetylase inhibitor sodium butyrate (SB) has been inconclusive. The aim of this study was to examine the antidepressant-like effect of SB and elucidate its molecular mechanisms. Methods. We examined the antidepressant-like effect of SB in a forced swim test (FST) and a tail suspension test (TST). Hippocampal gene expression analyses using DNA microarray and real-time PCR were undertaken. Western blotting and ChIP assay were undertaken to examine whether histone acetylation was associated with changes in gene expression by SB. Results. Repeated administration of SB significantly reduced immobility on the FST and the TST, and significantly altered the levels of mRNA for several genes; e.g., upregulation of transthyretin (Ttr) and downregulation of serotonin 2A receptor (Htr2a). Western blotting and ChIP assay revealed selective increases in histone H4 acetylation at the promoter of the Ttr gene with a significant increase in Ttr immunoreactivity 24 h after the final administration of SB. Conclusion. These findings suggest the possibility that alterations in gene expression, including upregulation of Ttr and downregulation of several other genes, including Htr2a, may be involved in antidepressant-like effect of SB.

Key words::

• Antidepressant
• HDACi
• FST
• histone acetylation
• transthyretin

Acknowledgements

This study was supported by a grant-in-aid for general scientific research from the Ministry of Education, Science, and Culture of Japan, and a grant from Core Research for Evolutional Science and Technology (CREST) of Japan Science and Technology (JST). This paper has been carefully reviewed by an experienced medical editor whose first language is English at NAI Inc. and who is specialized in the editing of papers written by physicians and scientists whose native language is not English.

Statement of Interest

None.