Nrf2 regulates iron-dependent hippocampal synapses and functional connectivity damage in depression

Abstract

Neuronal iron overload contributes to synaptic damage and neuropsychiatric disorders. However, the molecular mechanisms underlying iron deposition in depression remain largely unexplored. Our study aims to investigate how nuclear factor-erythroid 2 (NF-E2)-related factor 2 (Nrf2) ameliorates hippocampal synaptic dysfunction and reduces brain functional connectivity (FC) associated with excessive iron in depression. We treated mice with chronic unpredictable mild stress (CUMS) with the iron chelator deferoxamine mesylate (DFOM) and a high-iron diet (2.5% carbonyl iron) to examine the role of iron overload in synaptic plasticity. The involvement of Nrf2 in iron metabolism and brain function was assessed using molecular biological techniques and in vivo resting-state functional magnetic resonance imaging (rs-fMRI) through genetic deletion or pharmacologic activation of Nrf2. The results demonstrated a significant correlation between elevated serum iron levels and impaired hippocampal functional connectivity (FC), which contributed to the development of depression-induced CUMS. Iron overload plays a crucial role in CUMS-induced depression and synaptic dysfunction, as evidenced by the therapeutic effects of a high-iron diet and DFOM. The observed iron overload in this study was associated with decreased Nrf2 levels and increased expression of transferrin receptors (TfR). Notably, inhibition of iron accumulation effectively attenuated CUMS-induced synaptic damage mediated by downregulation of brain-derived neurotrophic factor (BDNF). Nrf2−/− mice exhibited compromised FC within the limbic system and the basal ganglia, particularly in the hippocampus, and inhibition of iron accumulation effectively attenuated CUMS-induced synaptic damage mediated by downregulation of brain-derived neurotrophic factor (BDNF). Activation of Nrf2 restored iron homeostasis and reversed vulnerability to depression. Mechanistically, we further identified that Nrf2 deletion promoted iron overload via upregulation of TfR and downregulation of ferritin light chain (FtL), leading to BDNF-mediated synapse damage in the hippocampus. Therefore, our findings unveil a novel role for Nrf2 in regulating iron homeostasis while providing mechanistic insights into poststress susceptibility to depression. Targeting Nrf2-mediated iron metabolism may offer promising strategies for developing more effective antidepressant therapies.

Bergamot essential oil improves CUMS‐induced depression‐like behaviour in rats by protecting the plasticity of hippocampal neurons

“…Secondly, we believe that the difference of stress mode and time is also an important reason affecting the experimental results. 25 Moreover, we also found inhaling BEO increased dendritic length and spine density in the HIPP of CUMS-induced rats.…”

“…This is similar to the results of some studies in recent years, CUMS induced the decrease of dendrite length and spinal density in the brain region of depressed rats. 6,[22][23][24][25] Hei et al found that chronic mild stress increased the density of synpase and small spine in inner and outer in DG, 26 which may be strongly related to different types of animal models, because our research object is rats, while Hei et al's research object is mice.…”

Ferroptosis: a new antidepressant pharmacological mechanism

“…The results indicated higher expression levels of TF and TfR1 in the peripheral blood and brain of CSDS-induced depression mouse models compared to the control group ( CHANG et al, 2022 ). Further studies have demonstrated a strong correlation between the onset of depression and the reduction of hippocampal neuronal synapses, which is attributed to the upregulation of TfR1 and downregulation of FTL caused by nuclear factor erythroid-2 related factor 2 (Nrf2) deficiency ( ZENG et al, 2023 ). These findings align with the research conducted by Wang et al, whose team elucidated the association between iron deposition in the hippocampus and depression, along with confirming the reduction of FTH induced by lipopolysaccharide (LPS) in depressed mice ( WANG et al, 2021a ).…”

“…Neuroinflammation refers to the immune response of the central nervous system (CNS) mediated mainly by microglia and astrocytes in the hippocampus ( LEE and HYUN, 2023 ). Microglia, known for their high iron content ( UZUNGIL et al, 2022 ), have been implicated in depression associated with abnormal glial activation and iron overload, suggesting a potential connection between iron and neuroinflammation ( ZENG et al, 2023 ). However, the precise mechanism by which iron overload disrupts neurotransmitter homeostasis and induces anxiety and depressive behaviors remains unclear ( UZUNGIL et al, 2022 ).…”

“…Furthermore, Gao et al showed in a chronic unpredictable mild stress (CUMS) mouse model that iron deposition in microglia within the hippocampus is closely associated with neuronal degeneration and death ( GAO W. et al, 2019 ). Additionally, Zeng et al highlighted the significant role of Nrf2 as an anti-inflammatory factor in regulating iron deposition and neuroinflammatory responses in depression ( ZENG et al, 2023 ). In a comparative study using hippocampal proteomics, Cao et al observed distinct protein expression differences between normal mice and CUMS model mice, indicating pronounced activation of neuronal necrosis and iron deposition in the hippocampus, thus promoting the occurrence of depression ( CAO et al, 2021 ).…”