Methyl-CpG binding protein 2 (MeCP2) is a basic nuclear protein involved in the regulation of gene expression and microRNA processing. Duplication of MECP2-containing genomic segments causes MECP2 duplication syndrome, a severe neurodevelopmental disorder characterized by intellectual disability, motor dysfunction, heightened anxiety, epilepsy, autistic phenotypes, and early death. Reversal of the abnormal phenotypes in adult mice with MECP2 duplication (MECP2-TG) by normalizing the MeCP2 levels across the whole brain has been demonstrated. However, whether different brain areas or neural circuits contribute to different aspects of the behavioral deficits is still unknown. Here, we found that MECP2-TG mice showed a significant social recognition deficit, and were prone to display aversive-like behaviors, including heightened anxiety-like behaviors and a fear generalization phenotype. In addition, reduced locomotor activity was observed in MECP2-TG mice. However, appetitive behaviors and learning and memory were comparable in MECP2-TG and wild-type mice. Functional magnetic resonance imaging illustrated that the differences between MECP2-TG and wild-type mice were mainly concentrated in brain areas regulating emotion and social behaviors. We used the CRISPR-Cas9 method to restore normal MeCP2 levels in the medial prefrontal cortex (mPFC) and bed nuclei of the stria terminalis (BST) of adult MECP2-TG mice, and found that normalization of MeCP2 levels in the mPFC but not in the BST reversed the social recognition deficit. These data indicate that the mPFC is responsible for the social recognition deficit in the transgenic mice, and provide new insight into potential therapies for MECP2 duplication syndrome.

中文翻译：

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通过内侧前额叶皮层中MeCP2的标准化逆转具有MECP2复制的成年小鼠的社交认知缺陷。

甲基-CpG结合蛋白2（MeCP2）是一种基本的核蛋白，参与基因表达和microRNA加工的调控。包含MECP2的基因组片段的重复引起MECP2复制综合征，这是一种严重的神经发育障碍，其特征是智力残疾，运动功能障碍，焦虑加剧，癫痫，自闭症表型和早期死亡。已经证明通过使整个脑中的MeCP2水平正常化，可以逆转成年小鼠的MECP2重复（MECP2 -TG）异常表型。但是，尚不清楚是不同的大脑区域还是神经回路导致了行为缺陷的不同方面。在这里，我们发现MECP2-TG小鼠表现出显着的社交认知缺陷，并且容易表现出厌恶样行为，包括加剧的焦虑样行为和恐惧泛化表型。另外，在MECP2 -TG小鼠中观察到运动活性降低。但是，在MECP2 -TG和野生型小鼠中，食欲行为和学习记忆力是可比的。功能磁共振成像表明，MECP2 -TG与野生型小鼠之间的差异主要集中在调节情绪和社交行为的大脑区域。我们使用CRISPR-Cas9方法恢复了成年MECP2的内侧前额叶皮层（mPFC）和终末纹的床核（BST）中的正常MeCP2水平-TG小鼠，发现在mPFC中而不是在BST中MeCP2水平的正常化逆转了社会认知缺陷。这些数据表明，mPFC负责转基因小鼠的社会认知缺陷，并为MECP2复制综合征的潜在疗法提供了新的见识。