Abstract：
Mutations in the SRCAP gene are among the genetic alterations identified in autism spectrum disorders (ASD). However, the pathogenic mechanisms remain unclear. In this study, we demonstrate that Srcap+/- mice manifest deficits in social novelty response, as well as increased repetitive behaviors, anxiety, and impairments in learning and memory. Notably, a reduction in parvalbumin-positive neurons is observed in the retrosplenial cortex (RSC) and dentate gyrus (DG) of these mice. Through RNA sequencing, we identify dysregulation in 27 ASD-related genes in Srcap+/- mice. Specifically, we find that Srcap regulates expression of Satb2 via H2A.z in the promoter. Therapeutic intervention via retro-orbital injection of adeno-associated virus (AAV)-Satb2 in neonatal Srcap+/- mice leads to amelioration of the neurodevelopmental and ASD-like abnormalities. Furthermore, the expression of Satb2 only in the RSC of adolescent mice rectifies social novelty impairments. These results underscore the pivotal role of Srcap in neurodevelopment, by regulating Satb2, providing valuable insights for the pathophysiology of ASD.
摘要：
SRCAP基因的突变是在自闭症谱系障碍（ASD）中鉴定的遗传改变之一。然而,致病机制尚不清楚。在这项研究中,我们证明Srcap+/-小鼠在社会新颖性反应中表现出缺陷，以及增加的重复行为，焦虑,学习和记忆障碍。值得注意的是,在这些小鼠的脾后皮质(RSC)和齿状回(DG)中观察到小白蛋白阳性神经元的减少。通过RNA测序，我们在Srcap+/-小鼠中鉴定了27个ASD相关基因的失调。具体来说,我们发现Srcap通过H2A调节Satb2的表达。z在启动子中。通过在新生Srcap/-小鼠中眶后注射腺相关病毒（AAV）-Satb2的治疗干预导致神经发育和ASD样异常的改善。此外，Satb2仅在青春期小鼠的RSC中的表达纠正了社交新颖性损害。这些结果强调了Srcap在神经发育中的关键作用，通过调节Satb2，为ASD的病理生理学提供有价值的见解。
