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.

Prader–Willi syndrome (PWS) and Schaaf–Yang syndrome (SYS) share overlapping phenotypic features, but potential cardiac involvement in both conditions remains poorly understood. Here, we investigated cardiac function in Magel2 knockout (KO) mice, a model relevant to PWS and SYS, to assess the impact of Magel2 deficiency on the heart. Echocardiographic analysis of 20-week-old Magel2-KO mice revealed concentric remodeling of the left ventricle together with reduced left ventricular end-diastolic volume and stroke volume, as well as a modest but significant reduction in ejection fraction. Electrophysiological studies identified sex-dependent alterations, particularly in males, characterized by shortened action potential duration and increased atrial potassium currents. Surface electrocardiography recordings showed no overt arrhythmias and visual inspection confirmed sinus rhythm during the monitoring period; however, the observed cellular alterations indicate increased arrhythmogenic susceptibility. In addition, aged Magel2-KO mice developed adult-onset obesity and exhibited elevated HbA1c levels consistent with impaired glycemic control. Given the minimal expression of Magel2 in cardiac tissue, these findings suggest that systemic and metabolic alterations may contribute to the observed cardiac phenotype. Together, these results demonstrate structural cardiac remodeling and electrophysiological changes consistent with increased arrhythmogenic susceptibility in Magel2-deficient mice, suggesting clinically relevant cardiac involvement in SYS and PWS. Our findings support consideration of structured cardiovascular monitoring to mitigate potential secondary cardiac complications in affected individuals.

FOXP1 syndrome caused by FOXP1 haploinsufficiency is characterized by intellectual disability, speech, and language impairment, autistic features, and neuropsychiatric abnormalities such as anxiety and hyperactivity. Behavioral changes in patients are mirrored in Foxp1 ^± mice. It is shown that decreased Foxp1 in the Foxp1 ^± striatum results in a significant decrease in phosphodiesterase 10a (Pde10a). Predominantly expressed in medium spiny neurons (MSNs), Pde10a modulates basal ganglia circuitry. Furthermore, the Foxp1 ^± striatum exhibits microglial activation, reduced synaptic pruning, and dysregulation of 111 inflammatory genes. These include the downregulated P2ry12 and Fcrls , markers of homeostatic microglia, and upregulated Cd74 , a marker of reactive microglia, suggesting that neuroinflammation contributes to the observed deficits. Interestingly, treatment of Foxp1 ^± mice with the PDE10A antagonist MP‐10 (PF‐2545920) immediately after birth not only corrects behavioral abnormalities, including decreased ultrasonic vocalization, hyperactivity, and anxiety but also normalizes changes in microglia morphology and synaptic pruning. Transcriptomic analysis with a neuroinflammation‐specific gene panel reveals nominal gene expression changes after MP‐10 treatment, including Bdnf upregulation and enrichment of neurotrophin signaling. Since FOXP1 and its signaling pathway are highly conserved, administration of MP‐10 or other Pde10a antagonists may also alleviate the neurological dysfunction seen in humans with FOXP1 syndrome.