Excess copper compromises hippocampal function in major depressive disorder: a study on clinical and animal evidence

Dysregulation of copper (Cu) metabolism may contribute to the pathogenesis of major depressive disorder (MDD) by disrupting hippocampal function. The aim of this study is to elucidate the neurobiological mechanisms through integrated clinical and animal experiments. A total of 85 MDD patients and 65 healthy controls (HCs) were recruited for this study. Serum Cu, ceruloplasmin (Cp) levels, and the relative mRNA expression of ATPase copper-transporting alpha (Atp7a) were measured. All participants underwent resting-state functional magnetic resonance imaging, and the Amplitude of Low-Frequency Fluctuation (ALFF) was calculated using subdivisions of the hippocampus (HPC). Cognitive function across seven domains was also assessed. In animal studies, mice were subjected to a chronic unpredictable mild stress (CUMS) model to develop depression. The Cu chelator tetrathiomolybdate (TTM) was then administered to investigate its impacts on Cu-related biochemical indices and brain structure in the HPC of the test group. We found that MDD patients exhibited increased serum Cu 2+ levels, and decreased Cp level and Atp7a mRNA expression compared to HCs. A significant reduction in ALFF was observed in the right rostral hippocampus (rHPC) of MDD patients. Animal studies showed depressive-like mice had high Cu levels and Atp7a mRNA expression, with low Cp levels in HPC, accompanying hippocampal cytoarchitectural impairments. Systemic administration of Cu TTM effectively counteracted and reversed both the Cu dyshomeostasis and hippocampal structural damage associated with depression. Patients with MDD exhibit Cu metabolism dysregulation, with excess Cu²⁺ harming hippocampal neurons and contributing to the pathogenesis of depression. Consequently, modulating Cu homeostasis may represent a novel therapeutic target for MDD.