Development of a treatment to alleviate symptoms of FOXP1 syndrome

• Applicant: Dr. Henning Fröhlich, Ph.D.
• Subject Area: Human Genetics
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 517366075

The goal of my study is the detailed investigation of a treatment against symptoms of FOXP1 syndrome using a specific mouse model, with a view to transferability to humans. This genetic disorder, which is based on a FOXP1 haploinsufficiency, is characterized by autism spectrum disorder, intellectual disability and speech and language deficits. In addition, many of these patients exhibit neuropsychiatric abnormalities. Causal therapy does not exist, and the neuroleptics approved for autism, as well as medications to alleviate anxiety disorders, hyperactivity, or obsessive-compulsive disorder, not only have severe side effects, but there is little evidence of their benefit. Using Foxp1+/- mice, we demonstrated that the loss of one Foxp1 copy leads to decreased expression of striatal phosphodiesterase 10a (Pde10a). Inhibition of this enzyme by specific antagonists has already proven useful in animal models of schizophrenia as well as Huntington's and Parkinson's disease - disorders of the basal ganglia that are also associated with reduced PDE10a expression. Since behavioral abnormalities in Foxp1+/- mice are already observed in the first postnatal days, the extent to which daily administration of a Pde10a antagonist from birth improves the animals' symptomatology was tested. In contrast to untreated animals, treated animals had a normal number of ultrasonic calls and did not show increased anxiety behavior and hyperactivity. Therefore, this compound may also have a positive effect on behavioral changes and motor deficits in FOXP1 syndrome. However, FOXP1 syndrome is not usually diagnosed immediately after birth. Therefore, I would like to investigate whether treatment at later developmental stages also alleviates the existing deficits and, in this context, test in vivo how different treatment periods affect the activity of striatal projection neurons of the direct and indirect pathways. Furthermore, I am interested in the influence of the antagonist on the transcriptome of these two neuron populations and the microglia in three different subregions of the striatum and whether the impaired mitochondrial function of Foxp1+/- animals improves after treatment. In addition, a three-dimensional reconstruction of the morphology of microglia and astrocytes in the striatum will provide information on whether the antagonist influences the activation state of these cells and thus positively affects possible neuroinflammation in the Foxp1+/- brain. My study is a first step towards a specific treatment for FOXP1 syndrome that may achieve better results than currently used compounds.

• DFG Programme: Research Grants