FOXP1 syndrome caused by haploinsufficiency of the forkhead box protein P1 (FOXP1) gene 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-1α, Tfam, Opa1, and Drp1) were dysregulated in the striatum of Foxp1+/− mice at different postnatal stages. Furthermore, these animals exhibit a reduced mitochondrial membrane potential and complex I activity, as well as decreased expression of the antioxidants superoxide dismutase 2 (Sod2) and glutathione (GSH), resulting in increased oxidative stress and lipid peroxidation. 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 underlie the cognitive and motor impairment in FOXP1 deficiency.

Reduced cognitive flexibility, characterized by restricted interests and repetitive behavior, is associated with atypical memory performance in autism spectrum disorder (ASD), suggesting hippocampal dysfunction. FOXP1 syndrome is a neurodevelopmental disorder characterized by ASD, language deficits, global developmental delay, and mild to moderate intellectual disability. Strongly reduced Foxp1 expression has been detected in the hippocampus of Foxp1+/− mice, a brain region required for learning and memory. To investigate learning and memory performance in these animals, fear conditioning tests were carried out, which showed impaired associative learning compared with wild type (WT) animals. To shed light on the underlying mechanism, we analyzed various components of the mitochondrial network in the hippocampus. Several proteins regulating mitochondrial biogenesis (e.g., Foxo1, Pgc-1α, Tfam) and dynamics (Mfn1, Opa1, Drp1 and Fis1) were significantly dysregulated, which may explain the increased mitophagy observed in the Foxp1+/− hippocampus. The reduced activity of complex I and decreased expression of Sod2 most likely increase the production of reactive oxygen species and the expression of the pre-apoptotic proteins Bcl-2 and Bax in this tissue. In conclusion, we provide evidence that a disrupted mitochondrial network and the resulting oxidative stress in the hippocampus contribute to the altered learning and cognitive impairment in Foxp1+/− mice, suggesting that similar alterations also play a major role in patients with FOXP1 syndrome.

Background. Recent studies have shown that Ras-like without CAAX2 (RIT2) polymorphism is a susceptible factor for Parkinson’s disease (PD) and autism spectrum disorder (ASD). SNP rs12456492 and rs16976358 show the emerging evidence of increased risk of PD and ASD, respectively. A meta-analysis examining the relationship between rs12456492 and PD was reported, but the association between rs16976358 and ASD has not been investigated. Methods. We searched literature from the databases PubMed, Embase, Google Scholar, ScienceDirect, EBSCOhost, OVID, Web of Science, and Wiley up to February 2021. Three studies including 1160 ASD cases and 1367 controls were eventually enrolled in the meta-analysis based on strict inclusion and exclusion criteria. Results. All genetics models indicate a significant association between rs16976358 polymorphism and ASD susceptibility (C vs. T: p = 0.001 ; CC vs. TT: p = 0.001 ; CT vs. TT: p = 0.009 ; CC+CT vs. TT: p = 0.001 ; CC vs. CT+TT: p = 0.001 ; TT+CC vs. CT: p = 0.013 ). The results of sensitivity analysis and publication bias of Begg’s and Egger’s tests were stable in the models of allele (C vs. T), codominant (CC vs. TT), dominant (CC+CT vs. TT), and recessive (CC vs. CT+TT). Conclusions. Our meta-analysis exhibits that the allele C, CC, and CT genotyping of rs16976358 suggest the risk for ASD, but additional studies using a large sample size and ethnically diverse populations need to be included in the future.