Mitochondrial dysfunction and oxidative stress contribute to cognitive and motor impairment in FOXP1 syndrome

Significance FOXP1 haploinsufficiency underlies cognitive and motor impairments in individuals with FOXP1 syndrome. Here, we show that mice lacking one Foxp1 copy exhibit similar behavioral deficits, which may be caused by striatal dysfunction. Indeed, Foxp1 +/− striatal medium spiny neurons display reduced neurite branching, and we show altered mitochondrial biogenesis and dynamics; increased mitophagy; reduced mitochondrial membrane potential, structure, and motility; and elevated oxygen species in the striatum of these animals. As FOXP1 is highly conserved, our data strongly suggest that mitochondrial dysfunction and excessive oxidative stress contribute to the motor and cognitive impairments seen in individuals with FOXP1 syndrome. Thus, mitochondrial homeostasis is critical for normal development and can explain deficits in neurodevelopmental disorders.