title: Epigenetic regulation of BDNF in the learned helplessness-induced animal model of depression.
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.
authors.affiliation: Department of Pharmacology, College of Medicine, National Cheng-Kung University, Tainan 701, Taiwan.
authors.forename: Chun-Lin
authors.initials: CL
authors.lastname: Su
authors.affiliation: Department of Pharmacology, College of Medicine, National Cheng-Kung University, Tainan 701, Taiwan.
authors.forename: Chun-Wei
authors.initials: CW
authors.lastname: Su
authors.affiliation: Department of Pharmacology, College of Medicine, National Cheng-Kung University, Tainan 701, Taiwan.
authors.forename: Ya-Hsin
authors.initials: YH
authors.lastname: Hsiao
authors.affiliation: Department of Pharmacology, College of Medicine, National Cheng-Kung University, Tainan 701, Taiwan. Electronic address: powu@mail.ncku.edu.tw.
authors.forename: Po-Wu
authors.initials: PW
authors.lastname: Gean
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D020148:Butyric Acid / Q000494:pharmacology / Q000627:therapeutic use; D003863:Depression / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000502:physiology*; D005091:Exons / Q000235:genetics; D006380:Helplessness, Learned; D019417:Hindlimb Suspension; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D007099:Imipramine / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D013550:Swimming / Q000523:psychology; D014635:Valproic Acid / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D056572:Histone Deacetylase Inhibitors; D034741:RNA, Small Interfering; D020148:Butyric Acid; D014635:Valproic Acid; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases; D007099:Imipramine
keywords: Brain derived neurotrophic factor; Depression; Epigenetics; Learned helplessness