Unraveling\nCopper Imbalance in Autism Spectrum Disorder:\nMechanistic Insights from the Valproic Acid Mouse Model

Abnormal copper (Cu) levels are often closely associated\nwith neurological\ndisorders including neurodevelopmental conditions, such as autism\nspectrum disorder (ASD). However, the mechanisms underlying the disruption\nof Cu homeostasis in critical organs, such as the brain, remain unclear.\nIn this study, we elucidated the molecular mechanisms of Cu imbalance\nin the brain of a valproic acid (VPA) mouse model along with the changes\nin specific metabolites. Significant alterations occurred in proteins\nassociated with primary Cu-related metabolism in specific regions\nof the brain (prefrontal cortex, amygdala, cerebellum, and hippocampus),\nresulting in a direct elevation of Cu ions within the brain tissues\n(control: 5.05 ± 0.61 μg/g vs model: 6.28 ± 0.81 μg/g, <i>p</i> = 0.015). Furthermore, the brain metabolic profiles revealed\nsignificant upregulation of lipids, particularly phospholipid metabolites.\nTypical neurotransmitters, for example, dopamine (DA) (<i>p</i> < 0.0001) and serotonin (5-HT) (<i>p</i> = 0.02) were\nupregulated in amygdala. Other small metabolites like glutathione\n(GSH) (<i>p</i> = 0.0004) also exhibited notable variation\nin brain. The potential impact of Cu toxicity on the signaling pathways\nof key metabolites was then evaluated, providing new insights into\nthe role of Cu in metabolism of neurotransmitters in the brain. Our\nfinding sheds molecular aberrations associated with essential element\nmetabolism in the brain, providing new elemental perspectives for\nunderstanding the pathogenic mechanisms underlying ASD.