Mitochondrial dysfunction and oxidative stress contribute to cognitive and motor impairment in FOXP1 syndrome
There is increasing evidence that mitochondrial homeostasis - influenced by both genetic and environmental factors - is crucial in neurodevelopment. FOXP1 syndrome is a neurodevelopmental disorder that manifests motor dysfunction, intellectual disability, autism and language impairment. In this study, we used a Foxp1+/- mouse model to address whether cognitive and motor deficits in FOXP1 syndrome are associated with mitochondrial dysfunction and oxidative stress. Here we show that genes with a role in mitochondrial biogenesis and dynamics (e.g. Foxo1, Pgc-1, Tfam, Opa1, and Drp1) were dysregulated in the striatum of Foxp1+/- mice at different postnatal stages. Furthermore, in the striatum of Foxp1+/- animals, mitochondrial membrane potential was disrupted, and reactive oxygen species, lipid peroxidation and cytochrome c release were significantly elevated. These features can explain the reduced neurite branching, learning and memory, endurance, and motor coordination that we observed in these animals. Taken together, we provide strong evidence of mitochondrial dysfunction in Foxp1+/- mice, suggesting that insufficient energy supply and excessive oxidative stress underlies the cognitive and motor impairment in FOXP1 deficiency.
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