hCyfip1 overexpression in the basolateral amygdala of mice

CYFIP1, a protein that interacts with FMRP and regulates protein synthesis and actin dynamics, is over-expressed in Dup15q syndrome as well as autism spectrum disorder (ASD). While CYFIP1 heterozygosity has been rigorously studied due to its loss in 15q11.2 deletion, Prader-Willi and Angelman syndrome, the effects of CYFIP1 over-expression, as is observed in patients with CYFIP1 duplication are less well understood. Here, we developed a mouse model of human CYFIP1 overexpression (CYFIP1 OE) to study the effects of excess CYFIP1 on rodent behavior and biological pathways. Extensive behavioral testing of CYFIP1 OE mice reveals no changes in the core behaviors related to ASD: social interactions and repetitive behaviors. However, we did observe mild learning deficits and an exaggerated fear response. Using RNA sequencing of the basolateral amygdala, a region associated with fear response, we observed changes in pathways related to cytoskeletal regulation, oligodendrocytes and myelination. We also identified GABA-A subunit composition changes in BLA neurons which are part of the fear conditioning neuronal circuit. Overall, this research identifies the behavioral and molecular consequences of CYFIP1 overexpression and how they contribute to the variable phenotype seen in Dup15q syndrome and in ASD patients with excess CYFIP1. Quant seq from the BLA of 16 controls and 15 hCYFIP1 over-expressing mice.CYFIP1蛋白是一种与脆性X智力低下蛋白（FMRP）相互作用，并调控蛋白质合成及肌动蛋白动态的蛋白质，在15q重复综合征（Dup15q syndrome）以及自闭症谱系障碍（ASD）中呈现过表达状态。由于CYFIP1基因在15q11.2缺失、普拉德-威利综合征（Prader-Willi syndrome）以及安格尔曼综合征（Angelman syndrome）中发生缺失，学界此前已对CYFIP1杂合状态开展了大量严谨的研究，但对于CYFIP1基因重复患者中观察到的过表达效应，目前尚缺乏充分的认知。本研究构建了人源CYFIP1过表达（CYFIP1 OE）小鼠模型，以探究过量CYFIP1对啮齿类动物行为及生物学通路的影响。对CYFIP1过表达小鼠开展的全面行为学测试显示，其与自闭症谱系障碍核心症状相关的社交互动与重复刻板行为并无异常改变。然而，本研究观察到了轻度的学习缺陷与夸张化的恐惧反应。通过对与恐惧反应相关的脑区——基底外侧杏仁核（basolateral amygdala, BLA）进行RNA测序分析，本研究发现了与细胞骨架调控、少突胶质细胞及髓鞘形成相关的通路发生表达变化。此外，本研究还鉴定出恐惧条件反射神经环路中的基底外侧杏仁核神经元内GABAA受体（GABA-A）亚基组成发生了改变。综上，本研究明确了CYFIP1过表达所带来的行为与分子层面后果，及其如何参与介导15q重复综合征与携带过量CYFIP1的自闭症谱系障碍患者所呈现的可变表型。本研究的测序数据来自16只对照组小鼠与15只人源CYFIP1过表达小鼠的基底外侧杏仁核组织。