Acute stress induced depressive-like phenotypes via epigenetic regulation of BDNF expression in hippocampus

Abstract

Major depression has been the most affected neuropsychiatric disorders in the world We focused on the epigenetic mechanisms for developing potential antidepressants in the future The reduction of BDNF expression in the pathophysiology of depressive-like behaviors has been extensively studied but the role of epigenetic regulation in major depression remained elusive We used learned helplessness animal model as the acute stressor and evaluated the depressive-like behaviors through different paradigms We compared learned-helplessness (LH) mice with learned-helplessness-resilient (LHR) groups in a series of experiments Firstly we observed increased expression of HDAC2 and HDAC5 along with decreased BDNF in depressive state of rodents Sodium valproate administrated in mice improved the depressive-like behaviors through enhancing BDNF Secondly there was significant increase of methylation on exon I III and IV which negatively correlated with decreased BDNF Then we further surveyed the key methylation factors- DNA methyltransferase 1 3a and 3b(DNMT1 3a 3b) In LH mice mRNA and protein level of DNMT1 and DNMT3a was elevated accompanied by the reduction of BDNF Therefore the potent DNMT inhibitor 5-azacytidine was used to evaluate the reversal of depressive-like behaviors and reduced BDNF expression Thirdly the modulation of BDNF 3’ UTR by miR-206 was carried out in vitro The data indicated that miR-206-3p preferentially bind to the vectors bearing mBDNF #3 suggesting a targeted position for interfering BDNF expression Cotransfection of mimics and inhibitors in vectors carrying mBDNF #3 displayed dose-dependent effects both in reporter assay and in BDNF expression In vivo experiments Cy3-AM206 was administrated in mice to verify the distribution of Cy3 fluorescence and beneficial effects on BDNF Both intranasal and intra-hippocampal injection of AM206 in mice exhibited a therapeutic effect through behavior and molecular modulation which was determined by decreased immobility time and enhanced BDNF Morphological alteration of dendritic spines and colocalization of synaptic protein markers was also used to support the favorable effects of AM206 Taken together; BDNF expression is dynamically regulated by epigenetics and has been referred to a potential therapeutic agent in treating psychiatric disorders in preclinical study

Date of Award	2018 Aug 31
Original language	English
Supervisor	Ya-Hsin Hsiao (Supervisor)