Foxp striatal compensation (ATAC-Seq). Foxp striatal compensation (ATAC-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 factorsFoxp1andFoxp2, 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 ofFoxp1,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 betweenFoxp1andFoxp2in the D1-SPNs. Overall design: The transcription factors Foxp1 and Foxp2 are both expressed in the D1-SPNs of the striatum. We used single nuclei assay for transposase-accessible chromatin sequencing (snATAC-Seq) in both juvenile (P9) mouse striatum to investigate how loss of one or both of these genes from the D1-SPNs alters chromatin accessibility.

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中发挥关键作用。在棘突投射神经元中表达的调控转录因子发生突变，可引发神经发育障碍（NDDs）。在表达多巴胺受体1（D1）的棘突投射神经元中均有表达的旁系同源转录因子Foxp1与Foxp2，其变异体已被证实与神经发育障碍相关。本研究利用D1-SPN特异性敲除Foxp1、Foxp2或同时敲除两者的小鼠模型，并结合行为学实验、电生理学检测以及单细胞核RNA测序（snRNA-seq）、单细胞核转座酶可及性染色质测序（snATAC-seq）分析，发现同时敲除这两个基因会导致小鼠出现运动与社交行为受损，同时使D1-SPN的放电活动增强。对snRNA-seq数据进行的差异基因表达分析显示，受影响的基因涉及自闭症风险相关通路、电生理特性改变以及神经元发育与功能调控。上述结果表明，Foxp1与Foxp2在D1-SPN中存在功能互补关系。实验整体设计：转录因子Foxp1与Foxp2均在纹状体D1-SPN中表达。本研究对幼年（出生后第9天，P9）小鼠纹状体开展单细胞核转座酶可及性染色质测序（snATAC-seq），探究D1-SPN中单个或两个基因的缺失如何改变染色质可及性。