Epigenetic regulation of BDNF in the learned helplessness-induced animal model of depression. (May 2016)

• Record Type: Journal Article
• Authors: Su, Chun-Lin; Su, Chun-Wei; Hsiao, Ya-Hsin; Gean, Po-Wu
• Is Part Of: Journal of psychiatric research. Volume 76(2016:May)
• Page Start: 101
• Page End: 110
• Publication Date: 2016-05
• Subjects: Learned helplessness -- Brain derived neurotrophic factor -- Depression -- Epigenetics; Psychiatry -- Periodicals; Mental Disorders -- Periodicals; Maladies mentales -- Périodiques; Psychiatry; Electronic journals; Periodicals; 616.89005
• DOI: 10.1016/j.jpsychires.2016.02.008
• Languages: English
• ISSNs: 0022-3956

Abstract

Abstract: Major depressive disorder (MDD), one of the most common mental disorders, is a significant risk factor for suicide and causes a low quality of life for many people. However, the causes and underlying mechanism of depression remain elusive. In the current work, we investigated epigenetic regulation of BDNF in the learned helplessness-induced animal model of depression. Mice were exposed to inescapable stress and divided into learned helplessness (LH) and resilient (LH-R) groups depending on the number they failed to escape. We found that the LH group had longer immobility duration in the forced swimming test (FST) and tail suspension tests (TST), which is consistent with a depression-related phenotype. Western blotting analysis and enzyme-linked immunosorbent assay (ELISA) revealed that the LH group had lower BDNF expression than that of the LH-R group. The LH group consistently had lower BDNF mRNA levels, as detected by qPCR assay. In addition, we found BDNF exon IV was down-regulated in the LH group. Intraperitoneal injection of imipramine or histone deacetylase inhibitors (HDACi) to the LH mice for 14 consecutive days ameliorated depression-like behaviors and reversed the decrease in BDNF. The expression of HDAC5 was up-regulated in the LH mice, and a ChIP assay revealed that the level of HDAC5 binding to the promoter region of BDNF exon IV was higher than that seen in other groups. Knockdown of HDAC5 reduced depression-like behaviors in the LH mice. Taken together, these results suggest that epigenetic regulation of BDNF by HDAC5 plays an important role in the learned helplessness model of depression. Highlights: Protein and mRNA levels of hippocampal BDNF was significantly lower in learned helplessness (LH) mice. Chronic imipramine or HDACi treatment could ameliorate depressive behavior and rescue decreased BDNF expression in LH mice. HDAC5 binding to promoter of Bdnf exon IV was significantly higher in LH than those of LH-R and control mice. Knockdown of HDAC5 expression prevented LH-induced depressive behaviors. These results suggest epigenetic regulation of BDNF plays an important role in the LH-induced depression.