Allemang-Grand Rylan, Ellegood Jacob, Spencer Noakes Leigh, Ruston Julie, Justice Monica, Nieman Brian J, Lerch Jason P
Mouse Imaging Centre, 25 Orde Street, Toronto, M5T 3H7 Ontario Canada.
Neurosciences and Mental Health, Hospital for Sick Children, 555 University Ave, Toronto, M5G 1X8 Ontario Canada.
Mol Autism. 2017 Jun 26;8:32. doi: 10.1186/s13229-017-0138-8. eCollection 2017.
Rett syndrome (RTT) is a neurodevelopmental disorder that predominantly affects girls. The majority of RTT cases are caused by de novo mutations in methyl-CpG-binding protein 2 (MECP2), and several mouse models have been created to further understand the disorder. In the current literature, many studies have focused their analyses on the behavioral abnormalities and cellular and molecular impairments that arise from Mecp2 mutations. However, limited efforts have been placed on understanding how Mecp2 mutations disrupt the neuroanatomy and networks of the brain.
In this study, we examined the neuroanatomy of male and female mice from the Mecp2, Mecp2, and Mecp2 mouse lines using high-resolution magnetic resonance imaging (MRI) paired with deformation-based morphometry to determine the brain regions susceptible to Mecp2 disruptions.
We found that many cortical and subcortical regions were reduced in volume within the brains of mutant mice regardless of mutation type, highlighting regions that are susceptible to Mecp2 disruptions. We also found that the volume within these regions correlated with behavioral metrics. Conversely, regions of the cerebellum were differentially affected by the type of mutation, showing an increase in volume in the mutant Mecp2 brain relative to controls and a decrease in the Mecp2 and Mecp2 lines.
Our findings demonstrate that the direction and magnitude of the neuroanatomical differences between control and mutant mice carrying Mecp2 mutations are driven by the severity of the mutation and the stage of behavioral impairments.
雷特综合征（RTT）是一种主要影响女童的神经发育障碍疾病。大多数雷特综合征病例是由甲基CpG结合蛋白2（MECP2）的新发突变引起的，并且已经创建了几种小鼠模型以进一步了解该疾病。在当前文献中，许多研究将分析重点放在了由Mecp2突变引起的行为异常以及细胞和分子损伤上。然而，在理解Mecp2突变如何破坏大脑的神经解剖结构和神经网络方面所做的努力有限。
在本研究中，我们使用高分辨率磁共振成像（MRI）结合基于变形的形态测量法，对来自Mecp2、Mecp2和Mecp2小鼠品系的雄性和雌性小鼠的神经解剖结构进行了检查，以确定易受Mecp2破坏影响的脑区。
我们发现，无论突变类型如何，突变小鼠大脑中的许多皮质和皮质下区域体积均减小，突出显示了易受Mecp2破坏影响的区域。我们还发现这些区域的体积与行为指标相关。相反，小脑区域受突变类型的影响存在差异，相对于对照组，突变的Mecp2小鼠大脑中该区域体积增加，而在Mecp2和Mecp2品系中体积减小。
我们的研究结果表明，携带Mecp2突变的对照小鼠和突变小鼠之间神经解剖学差异的方向和程度是由突变的严重程度和行为损伤阶段所驱动的。
