GSE130653
Cortical Foxp2 supports behavioral flexibility and developmental dopamine D1 receptor expression
FoxP2 encodes a forkhead box transcription factor required for the development of neural circuits underlying language, vocalization, and motor-skill learning. Recent genetic studies have associated FOXP2 variation with neurodevelopmental disorders (NDDs), and within the cortex, it is coexpressed and interacts with other NDD-associated transcription factors. Cortical Foxp2 is required in mice for proper social interactions, but its role in other NDD-relevant behaviors is unknown. Here, we characterized such behaviors and their potential underlying cellular and molecular mechanisms in cortex-specific Foxp2 conditional knockout mice. These mice showed deficits in reversal learning without increased anxiety or hyperactivity. In contrast, they emitted normal vocalizations save for a decrease in loudness of neonatal calls. These behavioral phenotypes were accompanied by decreases in cortical dopamine D1 receptor (D1R) expression at neonatal and adult stages, while general cortical development remained unaffected. Finally, using single-cell transcriptomics, we identified neonatal D1R-expressing cell types in frontal cortex and found changes in D1R cell type composition and gene expression upon cortical Foxp2 deletion. Together these data support a role for Foxp2 in the development of dopamine-modulated cortical circuits potentially relevant to NDDs. Overall design: We used fluorescence-activated cell sorting (FACS) followed by single-cell RNA sequencing (scRNA-seq) to genetically profile Drd1a-tdTomato+ or golli-t-eGFP+ frontal cortical neurons from P7 control and Emx1-Cre Foxp2 conditional knockout (cKO) mice. We compared cell type composition and gene expression profiles between control and cKO mice, using two independent replicates per genotype.