Background CYFIP1, a protein that interacts with FMRP and regulates protein synthesis and actin dynamics, is overexpressed 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 overexpression, as is observed in patients with CYFIP1 duplication, are less well understood. Methods We developed and validated a mouse model of human CYFIP1 overexpression (CYFIP1 OE) using qPCR and western blot analysis. We performed a large battery of behavior testing on these mice, including ultrasonic vocalizations, three-chamber social assay, home-cage behavior, Y-maze, elevated plus maze, open field test, Morris water maze, fear conditioning, prepulse inhibition, and the hot plate assay. We also performed RNA sequencing and analysis on the basolateral amygdala. Results Extensive behavioral testing in 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 basolateral amygdala neurons, which are essential components of the neural fear conditioning circuit. Conclusion 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.

中文翻译：

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CYFIP1的过表达增加了小鼠的恐惧反应，但不影响社交或重复性的行为表型。

背景CYFIP1是一种与FMRP相互作用并调节蛋白质合成和肌动蛋白动力学的蛋白质，在Dup15q综合征和自闭症谱系障碍（ASD）中过表达。尽管已经对CYFIP1杂合性进行了严格的研究，因为它在15q11.2缺失中缺失，但对于在CYFIP1重复患者中观察到的CYFIP1过表达的影响，Prader-Willi和Angelman综合征却鲜为人知。方法我们使用qPCR和Western blot分析方法开发并验证了人CYFIP1过表达的小鼠模型（CYFIP1 OE）。我们对这些小鼠进行了大量的行为测试，包括超声波发声，三腔社会化验，笼养行为，Y型迷宫，高架加迷宫，开阔地测试，莫里斯水迷宫，恐惧条件，预脉冲抑制和热板测定。我们还对基底外侧杏仁核进行了RNA测序和分析。结果在CYFIP1 OE小鼠中进行的广泛行为测试表明，与ASD相关的核心行为没有改变：社交互动和重复性行为。但是，我们确实观察到轻度的学习缺陷和夸张的恐惧反应。使用基底外侧杏仁核（与恐惧反应相关的区域）的RNA测序，我们观察到了与细胞骨架调节，少突胶质细胞和髓鞘形成有关的途径的变化。我们还确定了基底外侧杏仁核神经元中的GABA-A亚基组成变化，这是神经恐惧调节电路的重要组成部分。结论总体而言，