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

作者：Ting Zeng, Junjie Li, Lingpeng Xie, Zhaoyang Dong, Qing Chen, Sha Huang, Shuwen Xie, Yuqi Lai, Jun Li, Weixin Yan, Yuhua Wang, Zeping Xie, Changlei Hu, Jiayi Zhang, Shanshan Kuang, Yuhong Song, Lei Gao, Zhiping Lv · 发表于：Journal of Neuroinflammation · 年份：2023 · DOI：10.1186/s12974-023-02875-x · 被引用次数：66 · 研究领域：Tryptophan and brain disorders、Bipolar Disorder and Treatment、Stress Responses and Cortisol

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 mediat...