Abstract
FOXP1 syndrome is caused by FOXP1 haploinsufficiency and characterized by intellectual disability, speech and language impairment, autistic features and neuropsychiatric abnormalities such as anxiety and hyperactivity. Behavioral changes of respective patients are mirrored in Foxp1+/− mice. In this report, we demonstrate that decreased levels of Foxp1 in the Foxp1+/− striatum result in a significant decrease in phosphodiesterase 10a (Pde10a). Predominantly expressed in medium spiny neurons, Pde10a is involved in basal ganglia circuitry and cyclic nucleotide signalling. We also observed microglial activation and reduced synaptic pruning in the striatum of Foxp1+/− mice accompanied by an overexpression of inflammatory and microglia-associated genes (Rhoa, Cd74, Ifi30 and Fcgr2b). This suggests that neuroinflammation contributes to the observed cognitive and behavioral deficits. Interestingly, treatment of Foxp1+/− mice with the specific PDE10A/Pde10a antagonist MP-10 (PF-2545920) immediately after birth not only corrected the behavioral abnormalities, including decreased ultrasonic vocalization, hyperactivity, and increased anxiety but also normalized the changes in microglial morphology and synaptic pruning. Since FOXP1 and its signaling pathway are highly conserved, we hypothesize that administration of MP-10 or other Pde10a antagonists may also alleviate the neurological dysfunction seen in humans with FOXP1 syndrome. We also discuss how altered FOXP1 expression may be responsible for the reduced PDE10A levels in Huntington’s disease.