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

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.