Ahmed Newaz I, Khandelwal Nitin, Anderson Ashley G, Kulkarni Ashwinikumar, Gibson Jay, Konopka Genevieve
Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX 75390-9111, USA.
Peter O'Donnell Jr. Brain Institute, UT Southwestern Medical Center, Dallas, TX 75390-9111, USA.
bioRxiv. 2023 Jun 26:2023.06.26.546567. doi: 10.1101/2023.06.26.546567.
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 and , 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 , , or both and a combination of behavior, electrophysiology, and cell-type specific genomic analysis, loss of both genes results in impaired motor and social behavior as well as increased firing of the D1-SPNs. Differential gene expression analysis implicates genes involved in autism risk, electrophysiological properties, and neuronal development and function. Viral mediated re-expression of into the double knockouts was sufficient to restore electrophysiological and behavioral deficits. These data indicate complementary roles between and in the D1-SPNs.
纹状体的棘状投射神经元（SPN）在整合神经化学信息以协调基于运动和奖励的行为方面起着关键作用。在SPN中表达的调节转录因子发生突变可导致神经发育障碍（NDD）。已知在表达多巴胺受体1（D1）的SPN中均有表达的旁系同源转录因子 和 具有与NDD相关的变体。利用D1-SPN特异性缺失 、 或两者的小鼠，并结合行为学、电生理学和细胞类型特异性基因组分析，发现两个基因的缺失会导致运动和社交行为受损，以及D1-SPN的放电增加。差异基因表达分析表明，涉及自闭症风险、电生理特性以及神经元发育和功能的基因存在差异。病毒介导的 将 重新表达至双敲除小鼠中足以恢复电生理和行为缺陷。这些数据表明 和 在D1-SPN中具有互补作用。
