Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Psychological and Brain Sciences, Johns Hopkins University, Baltimore, MD 21218, USA.
Neurobiol Learn Mem. 2019 Nov;165:106962. doi: 10.1016/j.nlm.2018.11.007. Epub 2018 Nov 29.
Rett Syndrome (RTT) is a genetic disorder that is caused by mutations in the x-linked gene coding for methyl-CpG-biding-protein 2 (MECP2) and that mainly affects females. Male and female transgenic mouse models of RTT have been studied extensively, and we have learned a great deal regarding RTT neuropathology and how MeCP2 deficiency may be influencing brain function and maturation. In this manuscript we review what is known concerning structural and coinciding functional and behavioral deficits in RTT and in mouse models of MeCP2 deficiency. We also introduce our own corroborating data regarding behavioral phenotype and morphological alterations in volume of the cortex and striatum and the density of neurons, aberrations in experience-dependent plasticity within the barrel cortex and the impact of MeCP2 loss on glial structure. We conclude that regional structural changes in genetic models of RTT show great similarity to the alterations in brain structure of patients with RTT. These region-specific modifications often coincide with phenotype onset and contribute to larger issues of circuit connectivity, progression, and severity. Although the alterations seen in mouse models of RTT appear to be primarily due to cell-autonomous effects, there are also non-cell autonomous mechanisms including those caused by MeCP2-deficient glia that negatively impact healthy neuronal function. Collectively, this body of work has provided a solid foundation on which to continue to build our understanding of the role of MeCP2 on neuronal and glial structure and function, its greater impact on neural development, and potential new therapeutic avenues.
雷特综合征（RTT）是一种由 X 连锁基因编码的甲基-CpG 结合蛋白 2（MECP2）突变引起的遗传疾病，主要影响女性。RTT 的雄性和雌性转基因小鼠模型已被广泛研究，我们已经了解了 RTT 神经病理学以及 MeCP2 缺乏如何影响大脑功能和成熟的很多知识。在本文中，我们回顾了 RTT 和 MeCP2 缺乏的小鼠模型中已知的结构和功能以及行为缺陷，并介绍了我们自己关于皮层和纹状体体积、神经元密度、桶状皮层内经验依赖性可塑性的改变以及 MeCP2 缺失对神经胶质结构的影响的行为表型和形态改变的相关数据。我们的结论是，RTT 遗传模型中的区域结构变化与 RTT 患者大脑结构的改变非常相似。这些特定区域的改变通常与表型发作同时发生，并导致回路连接、进展和严重程度的更大问题。尽管 RTT 小鼠模型中观察到的改变似乎主要是由于细胞自主效应，但也存在非细胞自主机制，包括由 MeCP2 缺陷性神经胶质引起的机制，这些机制会对健康神经元功能产生负面影响。总之，这项工作为继续深入了解 MeCP2 对神经元和神经胶质结构和功能的作用、其对神经发育的更大影响以及新的潜在治疗途径提供了坚实的基础。
