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. 2021 Feb 24;11(1):140.
doi: 10.1038/s41398-021-01261-6.

Activation of BDNF by transcription factor Nrf2 contributes to antidepressant-like actions in rodents

Wei Yao #  1 , Song Lin #  2 , Jin Su  3 , Qianqian Cao  2 , Yueyue Chen  4 , Jiaxu Chen  1 , Zhentao Zhang  5 , Kenji Hashimoto  6 , Qi Qi  7 , Ji-Chun Zhang  8
Affiliations

Activation of BDNF by transcription factor Nrf2 contributes to antidepressant-like actions in rodents

Wei Yao et al. Transl Psychiatry. .

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.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Activation of Nrf2 inhibits BDNF transcriptional repressor (MeCP2, HDAC2, and mSin3a) expression in Neuro-2a cell.
A, B The quantitative real-time PCR for Nrf2 and Bdnf (mean ± SEM, n = 3 per group, one-way ANOVA, **p < 0.01 and ***p < 0.01). C The representative image for western blot. D The quantitative result for Nrf2. E The quantitative result for BDNF. F The quantitative result for HDAC2. G The quantitative result for mSin3A. H The quantitative result for MeCP2 (mean ± SEM, n = 3 per group, one-way ANOVA, *p < 0.05, **p < 0.01, and ***p < 0.01).
Fig. 2
Fig. 2. Nrf2 acts as transcription factor for BDNF.
A–E Nrf2 acted as a transcription factor for BDNF promoters. A, B BDNF exons I, II, and IV luciferase promoters and SFN or Nrf2 or siRNA-Nrf2 plasmids were treated into HEK293 cells (mean ± SEM, n = 4 per group, one-way ANOVA, *p < 0.05, **p < 0.01, ***p < 0.001, and # # #p < 0.001). C, D Results obtained using the luciferase plasmids containing mutation (Mut) at the Nrf2 binding motif of BDNF exon I promoter was compared with the wild type of promoters, respectively (mean ± SEM, n = 4 per group, one-way ANOVA, *p < 0.05, **p < 0.01, and ***p < 0.001). E ChIP-PCR assays demonstrated Nrf2 specifically bound to genomic DNA of BDNF exon I promoter binding motifs. The Nrf2 protein–DNA crosslinking samples were obtained from the HEK293 cells treated with SFN or Nrf2 plasmid or not (control) via co-immunoprecipitating with anti-Nrf2 antibodies. PCR was carried out by using primer pairs at BDNF exon I promoter. PCR assay also included each input sample. The positive control was demonstrated with anti-Histone H3 antibody coupling with GAPDH primers. F The immunofluorescence for Nrf2 and MeCP2. The SFN treated for Neuro-2a cell 24 h. The immunofluorescence was performed for Nrf2 and MeCP2. Scale bar 50 μm.
Fig. 3
Fig. 3. SFN shows beneficial effects for depression-like behavior by altering Nrf2, BDNF, HDAC2, mSin3a, MeCP2 expression, and attenuating the decrease of frequency of sEPSC and sIPSC in hippocampus and mPFC neurons.
A, B Western blot analysis for Nrf2, BDNF, and MeCP2 in mPFC and hippocampus (mean ± SEM, n = 4 per group, one-way ANOVA, *p < 0.05 and **p < 0.01). C The schedule of behavior test and treatment. D LMT: locomotion test, E TST: tail-suspension test, F FST: forced swimming test (mean ± SEM, n = 7 or 8 per group, one-way ANOVA, *p < 0.05, **p < 0.01). G Up: representative traces of sEPSC in hippocampal DG neurons. Scale bars represent 2 s, 20 pA. Down: histograms of sEPSC frequency in hippocampal DG neurons (mean ± SEM, n = 7–9 neurons of three mice per group, one-way ANOVA, *p < 0.05, **p < 0.01). H Up: representative traces of sEPSC in mPFC neurons. Scale bars represent 2 s, 20 pA. Down: histograms of sEPSC frequency in mPFC neurons (mean ± SEM, n = 8–10 neurons of three mice per group). I Up: representative traces of sIPSC in mPFC neurons. Scale bars represent 2 s, 50 pA. Down: histograms of sIPSC frequency in mPFC neurons (mean ± SEM, n = 8–10 neurons of three mice per group, one-way ANOVA, *p < 0.05, **p < 0.01).
Fig. 4
Fig. 4. Nrf2 KO mice show depression-like behavior, alter BDNF, HDAC2, mSin3a, and MeCP2 expression and frequency of sEPSC and sIPSC in hippocampus and mPFC neurons.
A, B The western blot analysis for mPFC and hippocampus. The western blot was performed for Nrf2, BDNF, HDAC2, mSin3A, and MeCP2 in mPFC and hippocampus (mean ± SEM, n = 4 per group, one-way ANOVA, *p < 0.05, **p < 0.01). C The behavior test for Nrf2 KO mice after the SFN treatment. D LMT: locomotion test, E TST: tail-suspension test, F FST: forced swimming test, G SPT: sucrose preference test (mean ± SEM, n = 8 per group, one-way ANOVA, *p < 0.05, **p < 0.01). H Left: representative traces of sEPSC in hippocampal DG neurons. Scale bars represent 2 s, 20 pA. Right: histograms of sEPSC frequency in hippocampal DG neurons (mean ± SEM, n = 10–11 neurons of three mice per group, one-way ANOVA, *p < 0.05, **p < 0.01). I Left: representative traces of sIPSC in mPFC neurons. Scale bars represent 2 s, 50 pA. Right: histograms of sIPSC frequency in mPFC neurons (mean ± SEM, n = 9–10 neurons of three mice per group, one-way ANOVA, *p < 0.05).
Fig. 5
Fig. 5. Resistance elevates Nrf2, BDNF expression and inhibits HDAC2, mSin3a, and MeCP2 expression.
A, B Schematic of social defeat stress model and the schedule of treatment. C Thermal imaging of mice trajectories. D The social interaction test for no target and target time (mean ± SEM, n = 4–6 per group, one-way ANOVA, *p < 0.05, **p < 0.01). E The ration for target and no target time (mean ± SEM, n = 4–6 per group, one-way ANOVA, *p < 0.05, **p < 0.01). E, F The western blot analysis for mPFC and hippocampus. The western blot was performed for Nrf2, BDNF, HDAC2, mSin3A, and MeCP2 in mPFC and hippocampus (mean ± SEM, n = 4 per group, one-way ANOVA, *p < 0.05, **p < 0.01). G The working model of Nrf2-induced BDNF transcription in the model of depression. Stress inhibits Nrf2 expression, which leads to inhibit BDNF transcriptional and abnormal synaptic transmission, causing depression-like behaviors in mice. SFN induces BDNF transcription by activating Nrf2 and could correct the abnormal synaptic transmission, resulting in antidepressant-like effects.
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