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

Area of Science:

• Neuroscience
• Toxicology
• Metabolism

Background:

• Copper (Cu) is vital but excessive exposure causes adverse health effects, including neurological dysfunction.
• Mechanisms underlying Cu-associated neurotoxicity, particularly in relation to depression, are not fully understood.

Purpose of the Study:

• To investigate the association between elevated serum Cu levels and depression-related symptoms.
• To elucidate the role of Lipin-1 and lipid accumulation in Cu-induced neurobehavioral deficits.

Main Methods:

• Population cohort analysis correlating serum Cu levels with depression symptoms.
• High-Cu diet (HCD) induction in mice to assess behavioral and hippocampal changes.
• In vitro studies using HT22 cells exposed to Cu, with Lipin-1 knockdown or inhibition.

Main Results:

• A positive association was found between high serum Cu levels and depression symptoms.
• HCD induced depression-like behaviors, cognitive impairment, and hippocampal lipid accumulation in mice.
• Lipin-1 knockdown ameliorated Cu-induced behavioral and pathological alterations in vivo and in vitro.
• Cu exposure increased Lipin-1 expression via mTORC1 activation, leading to lipid accumulation and neuronal injury.

Conclusions:

• Lipin-1-mediated lipid accumulation is a key mechanism in Cu-induced synaptic impairment and depression-like behaviors.
• The mTORC1/Lipin-1 signaling pathway is implicated in Cu-associated neurotoxicity.
• Cu contamination poses potential neurobehavioral risks through lipid-mediated pathways.