En2 knockout mice display neurobehavioral and neurochemical alterations relevant to autism spectrum disorder
En2 knockout mice display neurobehavioral and neurochemical alterations relevant to autism spectrum disorder
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DOI：
10.1016/j.brainres.2006.07.086
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发表时间：
2006-10-20
期刊：
影响因子：
2.9
通讯作者：
Wagner, George C.
中科院分区：
文献类型：
--
作者：
Cheh, Michelle A.;Millonig, James H.;Wagner, George C.
自闭症谱系障碍（ASD）是一种流行的、可遗传的神经发育障碍。最近的人类遗传学研究与同源框转录因子ENGRAPHY 2（EN 2）是ASD易感基因一致。En 2基因敲除小鼠（En 2（-/-））显示出与ASD大脑中观察到的相似的细微小脑神经病理学变化。为了研究En 2（-/-）小鼠是否表现出与ASD相关的异常行为，在设计用于评估社会成熟以及学习和记忆的任务中监测它们。在En 2（-/-）小鼠成熟过程中检测到社交行为缺陷，包括玩耍减少、社交嗅探和异理减少以及攻击性行为减少。在两个空间学习和记忆任务的缺陷也被观察到。由于自发活动是许多行为任务的组成部分，因此在不同的发育阶段进行测量。在敲除过程中，运动活动没有受到影响。然而，对En 2（-/-）小鼠的运动行为进行更彻底的分析显示，在特定的运动任务中存在缺陷。为了确定神经化学变化是否与这些行为表型相关，对特定脑区的单胺水平进行了评估。观察到小脑特异性5-羟色胺及其代谢产物增加。有趣的是，一些报告表明，5-羟色胺途径在ASD中受到影响。我们的结论是，En 2（-/-）小鼠显示行为和神经化学的变化，除了遗传和神经病理学的变化，相关的ASD。因此，这些小鼠可以用作自闭症的动物模型。(c)2006 Elsevier B. V.保留所有权利。
Autism spectrum disorder (ASD) is a prevalent and inheritable neurodevelopmental disorder. Recent human genetic studies are consistent with the homeobox transcription factor, ENGRAILED 2 (EN2), being an ASD susceptibility gene. En2 knockout mice (En2(-/-)) display subtle cerebellar neuropathological changes similar to what has been observed in the ASD brain. To investigate whether En2(-/-) mice displayed abnormal behavior relevant to ASD, they were monitored in tasks designed to assess social maturation as well as learning and memory. Deficits in social behavior were detected in En2(-/-) mice across maturation that included decreased play, reduced social sniffing and allogrooming, and less aggressive behavior. Deficits in two spatial learning and memory tasks were also observed. Because locomotor activity was a component of many of the behavioral tasks, this was measured at various stages of development. Locomotor activity was not compromised in the knockout. However, a more thorough analysis of motor behavior in En2(-/-) mice revealed deficits in specific motor tasks. To determine whether neurochemical changes were associated with these behavioral phenotypes, monoamine levels in specific brain regions were assessed. A cerebellar-specific increase in serotonin and its metabolite was observed. Interestingly, several reports have suggested that the serotonin pathway is affected in ASD. We conclude that En2(-/-) mice display behavioral and neurochernical changes, in addition to genetic and neuropathological changes, relevant to ASD. Therefore, these mice may be useful as an animal model of autism. (c) 2006 Elsevier B.V. All rights reserved.