A mouse model for MeCP2 duplication syndrome: MeCP2 overexpression impairs learning and memory and synaptic transmission.
A mouse model for MeCP2 duplication syndrome: MeCP2 overexpression impairs learning and memory and synaptic transmission.
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DOI：
10.1523/jneurosci.6000-11.2012
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发表时间：
2012-02-29
期刊：
影响因子：
--
通讯作者：
Monteggia LM
中科院分区：
文献类型：
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作者：
Na ES;Nelson ED;Adachi M;Autry AE;Mahgoub MA;Kavalali ET;Monteggia LM
Rett综合征和MECP 2复制综合征是分别由甲基-CpG结合蛋白2（MeCP 2）表达的功能丧失和功能获得改变引起的神经发育障碍。虽然已经有研究在动物模型中检查MeCP 2功能丧失，但在动物模型中关于MeCP 2过表达的信息有限。在这里，我们描述了MeCP 2过表达仅限于神经元（Tau-Mecp 2）的小鼠系。该MeCP 2过表达系显示运动协调缺陷、焦虑加剧以及伴随长时程增强和短时程突触可塑性缺陷的学习和记忆障碍。Tau-Mecp 2小鼠培养的海马神经元的全细胞电压钳记录显示微型兴奋性突触后电流的频率增加，而微型抑制性突触后电流没有变化，表明MeCP 2的过表达选择性地影响兴奋性突触功能。此外，我们发现，转录抑制机制的改变是Tau-Mecp 2小鼠海马神经元突触表型的基础。这些结果表明Tau-Mecp 2小鼠系重现了MECP 2复制综合征的许多关键表型，并支持使用这些小鼠进一步研究这种破坏性疾病。
Rett syndrome and MECP2 duplication syndrome are neurodevelopmental disorders that arise from loss of function and gain of function alterations in Methyl-CpG Binding Protein 2 (MeCP2) expression, respectively. Although there have been studies examining MeCP2 loss of function in animal models, there is limited information on MeCP2 overexpression in animal models. Here, we characterize a mouse line with MeCP2 overexpression restricted to neurons (Tau-Mecp2). This MeCP2 overexpression line shows motor coordination deficits, heightened anxiety, and impairments in learning and memory that are accompanied by deficits in long-term potentiation and short-term synaptic plasticity. Whole cell voltage clamp recordings of cultured hippocampal neurons from Tau-Mecp2 mice reveal augmented frequency of miniature excitatory postsynaptic currents with no change in miniature inhibitory postsynaptic currents indicating that overexpression of MeCP2 selectively impacts excitatory synapse function. Moreover, we show that alterations in transcriptional repression mechanisms underlie the synaptic phenotypes in hippocampal neurons from the Tau-Mecp2 mice. These results demonstrate the Tau-Mecp2 mouse line recapitulates many key phenotypes of MECP2 duplication syndrome and support the use of these mice to further study this devastating disorder.