Foxp striatal compensation (RNA-Seq)

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 Foxp1andFoxp2, 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 single-nuclei RNA (snRNA-seq) and single-nuclei Assay for Transposase-Accessible Chromatin sequencing (snATAC-seq), we find that loss of both genes results in impaired motor and social behavior as well as increased firing of the D1-SPNs. Differential gene expression analysis of snRNA-seq data implicates genes involved in autism risk, altered electrophysiological properties, and neuronal development and function. These data indicate complementary roles between Foxp1 and Foxp2 in the D1-SPNs. The transcription factors Foxp1 and Foxp2 are both expressed in the D1-SPNs of the striatum. We used single nuclei RNA sequencing (snRNA-Seq) in both juvenile (P9) and adult (P56) mouse striatum to test the effects of loss of one or both of these genes from the D1-SPNs.纹状体的棘突投射神经元（Spiny projection neurons, SPNs）在整合神经化学信息以协调运动与奖赏依赖行为的过程中发挥关键作用。SPNs中表达的调控性转录因子发生突变，可引发神经发育障碍（neurodevelopmental disorders, NDDs）。在表达多巴胺受体1（dopamine receptor 1, D1）的SPNs中均有表达的旁系同源转录因子Foxp1与Foxp2，其变异已被证实与神经发育障碍相关。本研究构建了D1-SPN特异性敲除Foxp1、Foxp2或同时敲除二者的小鼠模型，并结合行为学实验、电生理学检测以及单细胞核RNA测序（single-nuclei RNA sequencing, snRNA-seq）与单细胞核转座酶可及性染色质测序（single-nuclei Assay for Transposase-Accessible Chromatin sequencing, snATAC-seq）分析，发现同时敲除这两个基因会导致小鼠运动与社交行为受损，且D1-SPNs的神经元放电活动增强。对snRNA-seq数据开展的差异基因表达分析显示，自闭症易感相关基因、异常电生理特性相关基因以及神经元发育与功能相关基因均出现表达变化。上述结果表明，Foxp1与Foxp2在D1-SPNs中存在互补调控功能。转录因子Foxp1与Foxp2均在纹状体D1-SPNs中表达。本研究通过对幼年（出生后第9天，P9）与成年（出生后第56天，P56）小鼠的纹状体组织进行单细胞核RNA测序，以探究分别或同时敲除这两个基因对D1-SPNs的影响。