Foxp striatal compensation (ATAC-Seq)

Spiny projection neurons (SPNs) of the striatum are critical in integrating neurochemical information to coordinate motor and reward-based behavior. Mutations in the regulatory transcription factors expressed in SPNs can result in neurodevelopmental disorders (NDDs). Paralogous transcription factorsFoxp1andFoxp2, which are both expressed in the dopamine receptor 1 (D1) expressing SPNs, are known to have variants implicated in NDDs. Utilizing mice with a D1-SPN specific loss ofFoxp1,Foxp2, or both and a combination of behavior, electrophysiology, and single-nuclei RNA (snRNA-seq) and single-nuclei Assay for Transposase-Accessible Chromatin sequencing (snATAC-seq), we find that loss of both genes results in impaired motor and social behavior as well as increased firing of the D1-SPNs. Differential gene expression analysis of snRNA-seq data implicates genes involved in autism risk, altered electrophysiological properties, and neuronal development and function. These data indicate complementary roles betweenFoxp1andFoxp2in the D1-SPNs.