Functional investigations of Foxp1 and Foxp2 in Drd1 spiny projection neurons

项目摘要 FOXP 1或FOXP 2突变的个体有言语和语言缺陷和/或自闭症 谱系障碍（ASD）。小鼠中Foxp 1或Foxp 2的突变表现为ASD相关行为，例如 重复行为、发声改变和运动学习受损。最近的研究表明， 神经元细胞类型最有可能在与ASD相关的各种基因突变中被破坏，包括深 皮层神经元和纹状体多巴胺受体1（Drd 1）和多巴胺受体2（Drd 2）表达 棘状投射神经元（spiny projections neurons，SPNs）。FOXP 1在Drd 1和Drd 2 SPN中等效表达， FOXP 2在Drd 1 SPN中富集表达。研究发现，Foxp 1的Drd 2特异性敲除 导致Drd 2 SPN的特异性降低，Drd 2 SPN的内在兴奋性增加，运动功能缺陷， 学习和纹状体投射模式的改变。相反，在Drd 1 SPN中不需要Foxp 1表达 用于指定Drd 1 SPN、运动学习或适当的纹状体投射。Foxp 2的富集表达 在Drd 1 SPN中，可以补偿Foxp 1的损失。因此，我假设Foxp 1和Foxp 2 Drd 1 SPNs的补偿功能。使用Foxp 1、Foxp 2或两者的Drd 1靶向条件性敲除， 我将在两个目标中检验这个假设。在目标2中，我将测试对这些转录因子的需求 在运动相关（旋转棒，开放领域）和社会相关（社会互动，幼犬发声）行为。在 目的2，我将确定细胞特异性基因表达的变化与这些转录因子的损失， 比较多个相关时间点的单核RNA测序结果。成功 这些目标的完成将使人们更广泛地了解大脑中脆弱细胞类型的作用。 ASD的发展和病理生理学。此外，我将更深入地了解功能细胞- Foxp 1和Foxp 2的类型特异性作用，这两种转录因子在单基因原因中具有风险， 神经发育障碍，包括影响言语和语言发育的障碍。

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.