Functional investigations of Foxp1 and Foxp2 in Drd1 spiny projection neurons

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Project Summary Individuals with mutations in either FOXP1 or FOXP2 have speech and language deficits and/or autism spectrum disorder (ASD). Mutations of Foxp1 or Foxp2 in mice manifest in ASD-relevant behaviors, such as repetitive behaviors, altered vocalizations, and impaired motor learning. Recent studies have identified neuronal cell-types most likely to be disrupted across diverse genetic mutations linked to ASD, including deep layer cortical neurons and striatal dopamine receptor 1 (Drd1) and dopamine receptor 2 (Drd2) expressing spiny projections neurons (SPNs). FOXP1 is equivalently expressed in both Drd1 and Drd2 SPNs while FOXP2 has enriched expression in Drd1 SPNs. Studies have found that a Drd2 specific knockout of Foxp1 results in reduced specification of Drd2 SPNs, increased intrinsic excitability of Drd2 SPNs, deficits in motor learning, and altered striatal projection patterns. Conversely, Foxp1 expression in Drd1 SPNs is not required for specification of Drd1 SPNs, motor learning or proper striatal projections. The enriched expression of Foxp2 in Drd1 SPNs may compensate for the loss of Foxp1. I therefore hypothesize that Foxp1 and Foxp2 have compensatory functions in Drd1 SPNs. Using Drd1-targeted conditional knockout of Foxp1, Foxp2, or both, I will test this hypothesis in two Aims. In Aim 2, I will test the requirement for either of these transcription factors in motor relevant (rotarod, open field) and socially relevant (social interaction, pup vocalizations) behaviors. In Aim 2, I will determine cell-specific gene expression changes with loss of either of these transcription factors by comparing the results of single-nuclei RNA sequencing across multiple relevant time points. Successful completion of these aims will provide a broader understanding of the role of vulnerable cell-types in brain development and the pathophysiology of ASD. Moreover, I will gain a deeper insight into the functional cell- type-specific roles of Foxp1 and Foxp2, two transcription factors that are at risk in monogenic causes of neurodevelopmental disorders, including those that impact the development of speech and language.