Cortical Foxp2 Supports Behavioral Flexibility and Developmental Dopamine D1 Receptor Expression

Area of Science:

• Neuroscience
• Genetics
• Behavioral Science

Background:

• Genetic variations in FOXP2 are linked to speech and language disorders and neurodevelopmental disorders (NDDs).
• FoxP2 expression in the cortex persists from development through adulthood, but its precise functions remain largely uncharacterized.
• Understanding FoxP2's role is critical for neurodevelopmental disorder research.

Purpose of the Study:

• To investigate the specific functions of FoxP2 in the developing and adult cortex.
• To characterize the molecular and behavioral consequences of cortex-specific Foxp2 deletion.
• To explore the impact of Foxp2 on dopamine signaling and neuronal circuitry.

Main Methods:

• Generation and analysis of cortex-specific Foxp2 conditional knockout mice.
• Behavioral testing, including assessment of activity levels, anxiety, vocalizations, and reversal learning.
• Measurement of dopamine D1 receptor (D1R) expression in the cortex.
• Single-cell transcriptomics of neonatal frontal cortex to analyze cell type composition and gene expression.

Main Results:

• Cortex-specific Foxp2 knockout mice exhibited significant deficits in reversal learning, a measure of behavioral flexibility.
• No major changes were observed in general activity, anxiety, or vocalizations, except for reduced neonatal call loudness.
• Decreased cortical dopamine D1 receptor (D1R) expression was observed in both neonatal and adult knockout mice.
• Single-cell transcriptomics revealed altered D1R-expressing cell type composition and gene expression in the neonatal frontal cortex upon Foxp2 deletion, including non-cell-autonomous effects.

Conclusions:

• Foxp2 plays a critical role in the development of dopamine-modulated cortical circuits.
• Alterations in Foxp2 impact behavioral flexibility and dopamine D1 receptor signaling.
• These findings provide insights into the molecular mechanisms underlying neurodevelopmental disorders involving cortical dysfunction.