Unraveling Copper Imbalance in Autism Spectrum Disorder: Mechanistic Insights from the Valproic Acid Mouse Model

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