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Reversal of Social Recognition Deficit in Adult Mice with MECP2 Duplication via Normalization of MeCP2 in the Medial Prefrontal Cortex

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Abstract

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.

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Acknowledgements

We thank Wen-jing Chen and Kai-Wei Zhang, Institute of Neuroscience, Chinese Academy of Sciences, for assistance with fMRI data collection and advice on the manuscript. And we thank Zhi-Jiang Zhang and Sen Jin, Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, for help with the rabies virus tracing experiments. This work was supported by National Natural Science Foundation of China grants (31625013 and 91732302); a Shanghai Brain-Intelligence Project of the Science and Technology Commission of Shanghai Municipality (16JC1420501); and the Strategic Priority Research Program of the Chinese Academy of Sciences (XDBS01060200); Program of Shanghai Academic Research Leader, the Open Large Infrastructure Research of Chinese Academy of Sciences, and the Shanghai Municipal Science and Technology Major Project (2018SHZDZX05); and National Natural Science Foundation of China (81801354).

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Authors and Affiliations

  1. Institute of Neuroscience, State Key Laboratory of Neuroscience, Chinese Academy of Sciences Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China

    Bin Yu, Bo Yuan, Jian-Kun Dai, Tian-lin Cheng, Sheng-Nan Xia, Yi-Ting Yuan, Yue-Fang Zhang, Hua-Tai Xu, Zhi-Feng Liang & Zi-Long Qiu

  2. University of Chinese Academy of Sciences, Beijing, 100049, China

    Bin Yu & Sheng-Nan Xia

  3. Department of Molecular and Human Genetics, Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX, 77030, USA

    Ling-Jie He

  4. Wuhan Institute of Physics and Mathematics, Chinese Academy of Sciences, Wuhan, 430071, China

    Fu-Qiang Xu

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Yu, B., Yuan, B., Dai, JK. et al. Reversal of Social Recognition Deficit in Adult Mice with MECP2 Duplication via Normalization of MeCP2 in the Medial Prefrontal Cortex. Neurosci. Bull. 36, 570–584 (2020). https://doi.org/10.1007/s12264-020-00467-w

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