Compensation between FOXP transcription factors maintains proper striatal function

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Spiny projection neurons (SPNs) in the striatum integrate neurochemical signals crucial for motor and reward behaviors.
• Disruptions in transcription factors within SPNs are linked to neurodevelopmental disorders (NDDs).
• Foxp1 and Foxp2 are paralogous transcription factors expressed in D1-SPNs, with known associations with NDDs.

Purpose of the Study:

• To investigate the roles of Foxp1 and Foxp2 in D1-SPNs.
• To determine the impact of losing both Foxp1 and Foxp2 on behavior and neuronal function.
• To explore the potential for restoring gene function to correct deficits.

Main Methods:

• Generation of mice with D1-SPN-specific knockout of Foxp1, Foxp2, or both.
• Behavioral assessments (motor and social).
• Electrophysiological recordings.
• Cell-type-specific genomic analysis (differential gene expression).
• Viral-mediated gene re-expression.

Main Results:

• Loss of both Foxp1 and Foxp2 in D1-SPNs led to impaired motor and social behaviors.
• D1-SPNs showed increased firing rates in the double knockout mice.
• Gene expression analysis revealed alterations in genes associated with autism risk, electrophysiology, and neuronal development.
• Re-expression of Foxp1 rescued both electrophysiological and behavioral deficits.

Conclusions:

• Foxp1 and Foxp2 have complementary roles in D1-SPNs.
• These transcription factors are critical for normal motor and social behavior.
• Dysregulation of Foxp1/Foxp2 in D1-SPNs contributes to neurodevelopmental deficits, potentially through altered gene expression pathways.