Copper induces depressive-like behavior through neuronal lipid accumulation mediated by Lipin-1

Copper (Cu) is an essential trace element that plays a critical role in numerous biological processes. However, excessive Cu exposure has been associated with a range of adverse effects, including metabolic disturbances and neurological dysfunction in humans, while the underlying mechanisms remain incompletely understood. In the present study, we identified a positive association between elevated serum Cu levels and depression-related symptoms in a large population cohort. A high-Cu diet (HCD) induced depression-related behavioral phenotypes and mild cognitive impairment in mice, accompanied by impaired neuronal plasticity and neuronal lipid accumulation in the hippocampus. Notably, hippocampal knockdown of Lipin-1 markedly alleviated these behavioral and pathological alterations, including neuronal lipid accumulation and synaptic dysfunction induced by HCD exposure. Consistently, Cu exposure induced lipid accumulation and neuronal injury in HT22 cells in vitro, effects that were attenuated by Lipin-1 knockdown or pharmacological inhibition. Mechanistically, Cu increased Lipin-1 expression through activation of the mTORC1 signaling pathway. Collectively, our findings suggest that Lipin-1-mediated lipid accumulation contributes to synaptic impairment and depression-related behavioral phenotypes following excessive Cu exposure, highlighting the potential involvement of the mTORC1/Lipin-1 axis in Cu-associated neurotoxicity. SYNOPSIS: Cu contamination may pose neurobehavioral risks to humans by inducing lipid-mediated depressive-like behaviors.