MECP2倍增综合征小鼠神经环路机制研究的数据

甲基 CpG 结合蛋白 2（MeCP2）是一个基本的核蛋白，它可以参与基因表达的调控和小 RNA 的加工成熟。包含 MECP2 基因的基因组片段倍增可以导致MECP2 倍增综合症，它是一类严重的神经发育性疾病，主要表现为智力障碍，运动功能的失，焦虑的上升，癫痫，自闭症样的表型，以及过早死亡等。已经有报道表明，将大脑中的 MeCP2 恢复到正常水平，可以完全逆转 MECP2 倍增综合症模型小鼠中不正常的行为。但是，MeCP2 表达的上升是否特异性的影响了某些脑区或神经环路，以及脑区和神经环路的失调导致了特定的行为缺陷等问题目前依然不是十分清楚。在本研究中，我们发现 MECP2 倍增综合症的模
型小鼠倾向于表现出负向情绪相关的行为，包括减少的运动活性，升高的焦虑行为，社交认知的缺陷，以及恐惧泛化的表型。但是，奖赏相关的行为，新物体识别和空间学习记忆能力并没有明显的缺陷。功能核磁共振的数据也表明，MECP2倍增综合症的模型小鼠与野生型的小鼠相比，差异主要集中在调控负向情绪相关的脑区。我们利用 CRISPR-Cas9 的方法，在成年的 MECP2 倍增综合症模型小鼠中，将中央前额叶和终纹床核区域的 MeCP2 恢复到正常水平。我们发现，只有中央前额叶区域恢复正常 MeCP2 表达的转基因小鼠可以逆转社交认知缺陷的表型。进一步的，在狂犬病毒逆向跨突触示踪和电生理记录实验中，MECP2 倍增综合症的模型小鼠表现出从基底外侧杏仁核到中央前额叶的结构和功能输入的增加。有趣的是，我们利用药理遗传学技术抑制基底外侧杏仁核区域的锥体神经元并不能逆转转基因小鼠中的社交认知缺陷，却可以很好的逆转降低的运动活性和恐惧泛化的表型。这些数据表明，中央前额叶和基底外侧杏仁核区域 MeCP2的过表达可能分别贡献于社交认知缺陷和恐惧泛化表型，并且为MECP2 倍增综合症的治疗提供了新的思路。

Methyl-CpG-binding protein 2 (MeCP2) is an essential nuclear protein involved in the regulation of gene expression and the maturation processing of small RNAs. Genomic duplication of the MECP2 gene causes MECP2 duplication syndrome, a severe neurodevelopmental disorder primarily characterized by intellectual disability, loss of motor function, increased anxiety, epilepsy, autism-like phenotypes, and premature death. Previous studies have reported that restoring MeCP2 levels in the brain to normal can fully reverse abnormal behaviors in MECP2 duplication syndrome model mice. However, whether elevated MeCP2 expression specifically affects certain brain regions or neural circuits, and whether dysregulation of these brain regions and circuits leads to specific behavioral deficits, remains largely unclear. In this study, we found that MECP2 duplication syndrome model mice exhibit negative emotion-related behaviors, including reduced locomotor activity, heightened anxiety-like behaviors, social cognitive deficits, and fear generalization phenotypes. However, reward-related behaviors, novel object recognition, and spatial learning and memory abilities showed no significant impairments. Functional magnetic resonance imaging (fMRI) data also revealed that the differences between MECP2 duplication syndrome model mice and wild-type mice are mainly concentrated in brain regions regulating negative emotions. We used the CRISPR-Cas9 system to restore MeCP2 expression to normal levels in the medial prefrontal cortex (mPFC) and bed nucleus of the stria terminalis (BNST) of adult MECP2 duplication syndrome model mice. We found that only transgenic mice with restored MeCP2 expression in the mPFC could reverse the social cognitive deficit phenotype. Further experiments using rabies virus-mediated retrograde trans-synaptic tracing and electrophysiological recordings showed that MECP2 duplication syndrome model mice exhibit increased structural and functional inputs from the basolateral amygdala (BLA) to the mPFC. Interestingly, inhibiting pyramidal neurons in the BLA via pharmacogenetic techniques failed to reverse social cognitive deficits in the transgenic mice, but effectively reversed reduced locomotor activity and fear generalization phenotypes. These data suggest that MeCP2 overexpression in the mPFC and BLA respectively contributes to social cognitive deficits and fear generalization phenotypes, providing novel therapeutic insights for MECP2 duplication syndrome.

搜集汇总

背景与挑战

背景概述

该数据集研究MECP2倍增综合征的神经环路机制，使用转基因小鼠模型发现社交识别缺陷和异常行为表型，并通过CRISPR-Cas9技术揭示内侧前额叶皮层在逆转这些缺陷中的关键作用。数据集提供了关于MECP2基因重复如何影响大脑功能和行为的重要实验数据，为潜在疗法提供了新见解。