Genetic Effects on Cerebellar Structure Across Mouse Models of Autism Using a Magnetic Resonance Imaging Atlas
Genetic Effects on Cerebellar Structure Across Mouse Models of Autism Using a Magnetic Resonance Imaging Atlas
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DOI：
10.1002/aur.1344
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发表时间：
2014-02-01
期刊：
影响因子：
4.7
通讯作者：
Lerch, Jason P.
中科院分区：
文献类型：
--
作者：
Steadman, Patrick E.;Ellegood, Jacob;Lerch, Jason P.
自闭症人群的磁共振成像（MRI）被个体遗传和环境的固有异质性所混淆，这两个因素难以控制。成像遗传动物模型重现了与自闭症相关的突变，量化了遗传学对大脑形态的影响，并减轻了人类研究中的混淆因素。在这里，我们使用MRI对三种遗传小鼠模型进行成像，这些小鼠模型具有与自闭症有关的单一突变：Neuroligin-3 R451 C敲入，甲基-CpG结合蛋白-2（MECP 2）308-截短和整合素3纯合敲除。这项研究确定了小脑特有的形态差异，小脑是一种在人类神经成像和死后研究中反复与自闭症相关的结构。为了完成比较分析，创建分割的小脑模板并用于分割每个研究图像。这个模板描绘了39种不同的小脑结构。对于Neuroligin-3 R451 C雄性突变体，GII小叶的灰质（效应量（ES）=1.94，FDRq=0.03）和白色（ES=1.84，q=0.037）以及旁小叶的灰质（ES=1.45，q=0.045）的体积较大。MECP 2突变小鼠的小脑体积变化的范围增加，这取决于基因型：半合子男性纯合子女性。整合素3突变小鼠的小脑比对照组小得多，39个小脑结构中有28个小。这些成像结果进行了讨论，在自闭症的背景下，重复的行为，社交和学习。这项工作进一步阐明了小脑在自闭症中的作用。Autism Res 2014，7：124-137. (c)2013年国际自闭症研究学会，Wiley Periodicals，Inc。
Magnetic resonance imaging (MRI) of autism populations is confounded by the inherent heterogeneity in the individuals' genetics and environment, two factors difficult to control for. Imaging genetic animal models that recapitulate a mutation associated with autism quantify the impact of genetics on brain morphology and mitigate the confounding factors in human studies. Here, we used MRI to image three genetic mouse models with single mutations implicated in autism: Neuroligin-3 R451C knock-in, Methyl-CpG binding protein-2 (MECP2) 308-truncation and integrin 3 homozygous knockout. This study identified the morphological differences specific to the cerebellum, a structure repeatedly linked to autism in human neuroimaging and postmortem studies. To accomplish a comparative analysis, a segmented cerebellum template was created and used to segment each study image. This template delineated 39 different cerebellar structures. For Neuroligin-3 R451C male mutants, the gray (effect size (ES)=1.94, FDRq=0.03) and white (ES=1.84, q=0.037) matter of crus II lobule and the gray matter of the paraflocculus (ES=1.45, q=0.045) were larger in volume. The MECP2 mutant mice had cerebellar volume changes that increased in scope depending on the genotype: hemizygous males to homozygous females. The integrin 3 mutant mouse had a drastically smaller cerebellum than controls with 28 out of 39 cerebellar structures smaller. These imaging results are discussed in relation to repetitive behaviors, sociability, and learning in the context of autism. This work further illuminates the cerebellum's role in autism. Autism Res 2014, 7: 124-137. (c) 2013 International Society for Autism Research, Wiley Periodicals, Inc.