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

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.

• Authors: Bin Yu, Bo Yuan, Jian-Kun Dai, Tian-Lin Cheng, Sheng-Nan Xia, Ling-Jie He, Yi-Ting Yuan, Yue-Fang Zhang, Hua-Tai Xu, Fu-Qiang Xu, Zhi-Feng Liang, Zi-Long Qiu
• Journal: Neuroscience bulletin (Neurosci Bull) Vol. 36 Issue 6 Pg. 570-584 (Jun 2020) ISSN: 1995-8218 [Electronic] Singapore
• PMID: 32144612 (Publication Type: Journal Article)

Chemical References

• Mecp2 protein, mouse
• Methyl-CpG-Binding Protein 2

Topics

• Animals
• Anxiety
• China
• Disease Models, Animal
• Fear
• Gene Duplication
• Male
• Methyl-CpG-Binding Protein 2 (metabolism)
• Mice
• Mice, Transgenic
• Prefrontal Cortex (metabolism)
• Recognition, Psychology
• Social Behavior