Compensation between FOXP transcription factors maintains proper striatal function

• Published in: Cell reports (Cambridge) 2024-05, Vol.43 (5), p.114257-114257, Article 114257
• Main Authors: Ahmed, Newaz I., Khandelwal, Nitin, Anderson, Ashley G., Oh, Emily, Vollmer, Rachael M., Kulkarni, Ashwinikumar, Gibson, Jay R., Konopka, Genevieve
• Format: Article
• Language: English
• Subjects: Animals; autism; Corpus Striatum - metabolism; CP: Molecular biology; CP: Neuroscience; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; FOXP1; FOXP2; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; neurogenomics; Neurons - metabolism; Receptors, Dopamine D1 - genetics; Receptors, Dopamine D1 - metabolism; Repressor Proteins - genetics; Repressor Proteins - metabolism; Social Behavior; spiny projection neurons; striatum
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114257

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 factors Foxp1 and Foxp2, 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 of Foxp1, Foxp2, or both and a combination of behavior, electrophysiology, and cell-type-specific genomic analysis, loss of both genes results in impaired motor and social behavior as well as increased firing of the D1-SPNs. Differential gene expression analysis implicates genes involved in autism risk, electrophysiological properties, and neuronal development and function. Viral-mediated re-expression of Foxp1 into the double knockouts is sufficient to restore electrophysiological and behavioral deficits. These data indicate complementary roles between Foxp1 and Foxp2 in the D1-SPNs. [Display omitted] •Combined loss of Foxp1 and Foxp2 from D1-SPNs impairs motor and social behaviors in mice•Foxp1 and Foxp2 synergistically mediate D1-SPN excitability•Hundreds of genes in D1-SPNs are cooperatively regulated by both Foxp1 and Foxp2•Viral re-expression of Foxp1 is sufficient to rescue phenotypes in double knockouts Ahmed et al. show in mice that transcription factors Foxp1 and Foxp2 compensate for each other to maintain proper striatal function. This is evidenced by impairments in motor and social behavior, D1-SPN hyperexcitability, and identification of hundreds of differentially regulated genes in D1-SPNs upon loss of both Foxp1 and Foxp2.