Activation of BDNF by transcription factor Nrf2 contributes to antidepressant-like actions in rodents
Abstract The transcription factor erythroid 2-related factor 2 (Nrf2) and brain-derived neurotrophic factor (BDNF) play a key role in depression. However, the molecular mechanisms underlying the crosstalk between Nrf2 and BDNF in depression remain unclear. We examined whether Nrf2 regulates the tran...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2021-02-01
|
| Series: | Translational Psychiatry |
| Online Access: | https://doi.org/10.1038/s41398-021-01261-6 |
| _version_ | 1819183280961880064 |
|---|---|
| author | Wei Yao Song Lin Jin Su Qianqian Cao Yueyue Chen Jiaxu Chen Zhentao Zhang Kenji Hashimoto Qi Qi Ji-chun Zhang |
| author_facet | Wei Yao Song Lin Jin Su Qianqian Cao Yueyue Chen Jiaxu Chen Zhentao Zhang Kenji Hashimoto Qi Qi Ji-chun Zhang |
| author_sort | Wei Yao |
| collection | DOAJ |
| description | Abstract The transcription factor erythroid 2-related factor 2 (Nrf2) and brain-derived neurotrophic factor (BDNF) play a key role in depression. However, the molecular mechanisms underlying the crosstalk between Nrf2 and BDNF in depression remain unclear. We examined whether Nrf2 regulates the transcription of Bdnf by binding to its exon I promoter. Furthermore, the role of Nrf2 and BDNF in the brain regions from mice with depression-like phenotypes was examined. Nrf2 regulated the transcription of Bdnf by binding to its exon I promoter. Activation of Nrf2 by sulforaphane (SFN) showed fast-acting antidepressant-like effects in mice by activating BDNF as well as by inhibiting the expression of its transcriptional repressors (HDAC2, mSin3A, and MeCP2) and revising abnormal synaptic transmission. In contrast, SFN did not affect the protein expression of BDNF and its transcriptional repressor proteins in the medial prefrontal cortex (mPFC) and hippocampus, nor did it reduce depression-like behaviors and abnormal synaptic transmission in Nrf2 knockout mice. In the mouse model of chronic social defeat stress (CSDS), protein levels of Nrf2 and BDNF in the mPFC and hippocampus were lower than those of control and CSDS-resilient mice. In contrast, the protein levels of BDNF transcriptional repressors in the CSDS-susceptible mice were higher than those of control and CSDS-resilient mice. These data suggest that Nrf2 activation increases the expression of Bdnf and decreases the expression of its transcriptional repressors, which result in fast-acting antidepressant-like actions. Furthermore, abnormalities in crosstalk between Nrf2 and BDNF may contribute to the resilience versus susceptibility of mice against CSDS. |
| first_indexed | 2024-12-22T22:59:31Z |
| format | Article |
| id | doaj.art-1cf7d854e7564080a1089b622f27e18d |
| institution | Directory Open Access Journal |
| issn | 2158-3188 |
| language | English |
| last_indexed | 2024-12-22T22:59:31Z |
| publishDate | 2021-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Translational Psychiatry |
| spelling | doaj.art-1cf7d854e7564080a1089b622f27e18d2022-12-21T18:09:44ZengNature Publishing GroupTranslational Psychiatry2158-31882021-02-0111111210.1038/s41398-021-01261-6Activation of BDNF by transcription factor Nrf2 contributes to antidepressant-like actions in rodentsWei Yao0Song Lin1Jin Su2Qianqian Cao3Yueyue Chen4Jiaxu Chen5Zhentao Zhang6Kenji Hashimoto7Qi Qi8Ji-chun Zhang9Formula-Pattern Research Center, School of Traditional Chinese Medicine, Jinan UniversityDepartment of Physiology, School of Medicine, Jinan UniversityMOE Key Laboratory of Tumor Molecular Biology; Clinical Translational Center for Targeted Drug, Department of Pharmacology, School of Medicine, Jinan UniversityDepartment of Physiology, School of Medicine, Jinan UniversityGuangzhou Overseas Chinese Hospital of Jinan UniversityFormula-Pattern Research Center, School of Traditional Chinese Medicine, Jinan UniversityDepartment of Neurology, Renmin Hospital of Wuhan UniversityDivision of Clinical Neuroscience, Chiba University Center for Forensic Mental HealthMOE Key Laboratory of Tumor Molecular Biology; Clinical Translational Center for Targeted Drug, Department of Pharmacology, School of Medicine, Jinan UniversityDepartment of Physiology, School of Medicine, Jinan UniversityAbstract The transcription factor erythroid 2-related factor 2 (Nrf2) and brain-derived neurotrophic factor (BDNF) play a key role in depression. However, the molecular mechanisms underlying the crosstalk between Nrf2 and BDNF in depression remain unclear. We examined whether Nrf2 regulates the transcription of Bdnf by binding to its exon I promoter. Furthermore, the role of Nrf2 and BDNF in the brain regions from mice with depression-like phenotypes was examined. Nrf2 regulated the transcription of Bdnf by binding to its exon I promoter. Activation of Nrf2 by sulforaphane (SFN) showed fast-acting antidepressant-like effects in mice by activating BDNF as well as by inhibiting the expression of its transcriptional repressors (HDAC2, mSin3A, and MeCP2) and revising abnormal synaptic transmission. In contrast, SFN did not affect the protein expression of BDNF and its transcriptional repressor proteins in the medial prefrontal cortex (mPFC) and hippocampus, nor did it reduce depression-like behaviors and abnormal synaptic transmission in Nrf2 knockout mice. In the mouse model of chronic social defeat stress (CSDS), protein levels of Nrf2 and BDNF in the mPFC and hippocampus were lower than those of control and CSDS-resilient mice. In contrast, the protein levels of BDNF transcriptional repressors in the CSDS-susceptible mice were higher than those of control and CSDS-resilient mice. These data suggest that Nrf2 activation increases the expression of Bdnf and decreases the expression of its transcriptional repressors, which result in fast-acting antidepressant-like actions. Furthermore, abnormalities in crosstalk between Nrf2 and BDNF may contribute to the resilience versus susceptibility of mice against CSDS.https://doi.org/10.1038/s41398-021-01261-6 |
| spellingShingle | Wei Yao Song Lin Jin Su Qianqian Cao Yueyue Chen Jiaxu Chen Zhentao Zhang Kenji Hashimoto Qi Qi Ji-chun Zhang Activation of BDNF by transcription factor Nrf2 contributes to antidepressant-like actions in rodents Translational Psychiatry |
| title | Activation of BDNF by transcription factor Nrf2 contributes to antidepressant-like actions in rodents |
| title_full | Activation of BDNF by transcription factor Nrf2 contributes to antidepressant-like actions in rodents |
| title_fullStr | Activation of BDNF by transcription factor Nrf2 contributes to antidepressant-like actions in rodents |
| title_full_unstemmed | Activation of BDNF by transcription factor Nrf2 contributes to antidepressant-like actions in rodents |
| title_short | Activation of BDNF by transcription factor Nrf2 contributes to antidepressant-like actions in rodents |
| title_sort | activation of bdnf by transcription factor nrf2 contributes to antidepressant like actions in rodents |
| url | https://doi.org/10.1038/s41398-021-01261-6 |
| work_keys_str_mv | AT weiyao activationofbdnfbytranscriptionfactornrf2contributestoantidepressantlikeactionsinrodents AT songlin activationofbdnfbytranscriptionfactornrf2contributestoantidepressantlikeactionsinrodents AT jinsu activationofbdnfbytranscriptionfactornrf2contributestoantidepressantlikeactionsinrodents AT qianqiancao activationofbdnfbytranscriptionfactornrf2contributestoantidepressantlikeactionsinrodents AT yueyuechen activationofbdnfbytranscriptionfactornrf2contributestoantidepressantlikeactionsinrodents AT jiaxuchen activationofbdnfbytranscriptionfactornrf2contributestoantidepressantlikeactionsinrodents AT zhentaozhang activationofbdnfbytranscriptionfactornrf2contributestoantidepressantlikeactionsinrodents AT kenjihashimoto activationofbdnfbytranscriptionfactornrf2contributestoantidepressantlikeactionsinrodents AT qiqi activationofbdnfbytranscriptionfactornrf2contributestoantidepressantlikeactionsinrodents AT jichunzhang activationofbdnfbytranscriptionfactornrf2contributestoantidepressantlikeactionsinrodents |