Compensation between FOXP transcription factors maintains proper striatal function
Newaz I. Ahmed,
Nitin Khandelwal,
Ashley G. Anderson,
Emily Oh,
Rachael M. Vollmer,
Ashwinikumar Kulkarni,
Jay R. Gibson,
Genevieve Konopka
Affiliations
Newaz I. Ahmed
Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390-9111, USA; Peter O’Donnell Jr. Brain Institute, UT Southwestern Medical Center, Dallas, TX 75390-9111, USA
Nitin Khandelwal
Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390-9111, USA; Peter O’Donnell Jr. Brain Institute, UT Southwestern Medical Center, Dallas, TX 75390-9111, USA
Ashley G. Anderson
Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390-9111, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, TX 77030, USA
Emily Oh
Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390-9111, USA; Peter O’Donnell Jr. Brain Institute, UT Southwestern Medical Center, Dallas, TX 75390-9111, USA
Rachael M. Vollmer
Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390-9111, USA; Peter O’Donnell Jr. Brain Institute, UT Southwestern Medical Center, Dallas, TX 75390-9111, USA
Ashwinikumar Kulkarni
Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390-9111, USA; Peter O’Donnell Jr. Brain Institute, UT Southwestern Medical Center, Dallas, TX 75390-9111, USA
Jay R. Gibson
Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390-9111, USA; Peter O’Donnell Jr. Brain Institute, UT Southwestern Medical Center, Dallas, TX 75390-9111, USA
Genevieve Konopka
Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390-9111, USA; Peter O’Donnell Jr. Brain Institute, UT Southwestern Medical Center, Dallas, TX 75390-9111, USA; Corresponding author
Summary: 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.
