MeCP2 Is Critical for Maintaining Mature Neuronal Networks and Global Brain Anatomy during Late Stages of Postnatal Brain Development and in the Mature Adult Brain
MeCP2 Is Critical for Maintaining Mature Neuronal Networks and Global Brain Anatomy during Late Stages of Postnatal Brain Development and in the Mature Adult Brain
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DOI：
10.1523/jneurosci.1316-12.2012
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发表时间：
2012-07-18
影响因子：
5.3
通讯作者：
Ballas, Nurit
中科院分区：
文献类型：
--
作者：
Minh Vu Chuong Nguyen;Du, Fang;Ballas, Nurit
X连锁基因甲基-CpG结合蛋白2（Mecp2）的突变是多种神经精神疾病的基础，最常见的是瑞特综合征（RTT），这是一种严重的自闭症谱系障碍，大约每10000名女性活产婴儿中就有1人患病。由于Mecp2基因的突变发生在生殖细胞中，神经症状在儿童早期出现，因此MeCP2的作用被归因于特定发育阶段的大脑成熟。在此，我们发现如果在与RTT发病期相符的发育阶段或成年阶段在出生后去除MeCP2，小鼠会出现类似RTT症状的发病和进展的相似动力学过程，包括致死情况。我们首次表明在这两个不同阶段缺失MeCP2的大脑会主动萎缩，导致神经元细胞密度高于正常水平。此外，我们发现锥体神经元成熟的树突分支严重回缩，树突棘密度大幅降低。另外，海马星形胶质细胞的分支过程明显变得不那么复杂。这些变化伴随着几种突触蛋白水平的显著降低，包括CaMKII - / -、AMPA和NMDA受体，以及突触囊泡蛋白Vglut和Synapsin，它们是突触功能和树突分支结构的关键调节因子。重要的是，这些突触蛋白的mRNA水平保持不变，这表明MeCP2可能直接或间接在转录后调控这些突触蛋白。我们的数据表明MeCP2在出生后大脑发育后期对参与维持成熟神经网络的关键突触蛋白的转录后调控中起着至关重要的作用。
Mutations in the X-linked gene, methyl-CpG binding protein 2 (Mecp2), underlie a wide range of neuropsychiatric disorders, most commonly, Rett Syndrome (RTT), a severe autism spectrum disorder that affects approximately one in 10,000 female live births. Because mutations in the Mecp2 gene occur in the germ cells with onset of neurological symptoms occurring in early childhood, the role of MeCP2 has been ascribed to brain maturation at a specific developmental window. Here, we show similar kinetics of onset and progression of RTT-like symptoms in mice, including lethality, if MeCP2 is removed postnatally during the developmental stage that coincides with RTT onset, or adult stage. For the first time, we show that brains that lose MeCP2 at these two different stages are actively shrinking, resulting in higher than normal neuronal cell density. Furthermore, we show that mature dendritic arbors of pyramidal neurons are severely retracted and dendritic spine density is dramatically reduced. In addition, hippocampal astrocytes have significantly less complex ramified processes. These changes accompany a striking reduction in the levels of several synaptic proteins, including CaMKII-/-, AMPA, and NMDA receptors, and the synaptic vesicle proteins Vglut and Synapsin, which represent critical modifiers of synaptic function and dendritic arbor structure. Importantly, the mRNA levels of these synaptic proteins remains unchanged, suggesting that MeCP2 likely regulates these synaptic proteins post-transcriptionally, directly or indirectly. Our data suggest a crucial role for MeCP2 in post-transcriptional regulation of critical synaptic proteins involved in maintaining mature neuronal networks during late stages of postnatal brain development.