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journal article·2026-06-15Open access

Astrocytic FDX1 Contributes to Copper Dyshomeostasis‐associated Synaptic Dysfunction in Depression and Is Modulated by Exercise

Lina Gao, Rongji Hui, Zhibo Tang, Tao Feng, Zhihang Hu, Xiaoqing Zhang, Ping Jiang, Hui Zhao, Kwok‐Fai So, Tianyuan Luo, Yanzhou Chang, Lan Yan

Advanced Science
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Abstract

ABSTRACT Major depressive disorder (MDD) is increasingly linked to astrocyte dysfunction, yet how systemic metabolic disturbances contribute to glial alterations remains unclear. Disruption of trace metal homeostasis, particularly copper, has emerged as a potential contributor, but the underlying cellular mechanisms are poorly defined. Here, we integrate clinical data and mouse models to investigate the role of copper dyshomeostasis in depression. We show that copper levels are elevated in the systemic circulation of patients with MDD and in the prelimbic cortex (PrL) of stressed mice. In mice, copper accumulation is associated with increased astrocytic ferredoxin 1 (FDX1) expression, accompanied by reduced astrocyte number and structural complexity, impaired calcium signaling, and disrupted excitatory synaptic function. Astrocyte‐specific manipulations, in vivo calcium imaging, and electrophysiological recordings demonstrate that astrocytic FDX1 mediates the effects of copper imbalance on neural circuit dysfunction. Notably, physical exercise restores copper homeostasis, normalizes astrocytic FDX1 expression, improves astrocyte–neuron coupling, and alleviates depressive‐like behaviors. These findings identify an astrocyte‐mediated mechanism through which systemic copper imbalance influences neural function and provide insight into how exercise may mitigate depression‐related neural dysfunction.
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Research context

OpenAlex topics: Trace Elements in Health · Tryptophan and brain disorders · Ferroptosis and cancer prognosis

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

School of Mental Health Wenzhou Medical University Wenzhou China

College of Forensic Medicine Hebei Key Laboratory of Forensic Medicine Collaborative Innovation Center of Forensic Medical Molecular Identification Hebei Medical University Shijiazhuang China

Hebei Medical University Basic Medicine Postdoctoral Research Station Shijiazhuang China

Shanghai Mental Health Center School of Medicine Shanghai Jiao Tong University Shanghai China

Liver Transplantation Center Department of General Surgery Huashan Hospital Fudan University Shanghai China

Department of Psychiatry Ganzhou Hospital‐Nanfang Hospital Southern Medical University (Ganzhou People's Hospital) Ganzhou China

GHM Institute of CNS Regeneration Jinan University Guangzhou China

Department of Anesthesiology Affiliated Hospital of Zunyi Medical University Zunyi China

Key Laboratory of Anesthesia and Organ Protection of Ministry of Education (In Cultivation) Zunyi Medical University Zunyi China

College of Chemistry and Materials Science Jinan University Guangzhou China

Funding

National Natural Science Foundation of China · Natural Science Foundation of Shanghai Municipality · China Postdoctoral Science Foundation

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