Comprehensive analysis of a novel mouse model of the 22q11.2 deletion syndrome: a model with the most common 3.0-Mb deletion at the human 22q11.2 locus
Comprehensive analysis of a novel mouse model of the 22q11.2 deletion syndrome: a model with the most common 3.0-Mb deletion at the human 22q11.2 locus
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DOI：
10.1038/s41398-020-0723-z
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发表时间：
2020-02-05
影响因子：
6.8
通讯作者：
Aiba, Atsu
中科院分区：
文献类型：
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作者：
Saito, Ryo;Koebis, Michinori;Aiba, Atsu
22q11.2缺失综合征(22q11.2DS)与精神疾病的风险增加有关。虽然大多数22q11.2DS患者存在3.0-Mb缺失，但现有的小鼠模型仅模拟22q11.2DS的微小突变，即1.5-Mb缺失。存在于1.5-Mb缺失之外的基因在22q11.2DS的精神症状中的作用尚不清楚。在本研究中，我们使用CRISPR/Cas9系统建立了一个小鼠模型，该模型复制了22q11.2DS(Del(3.0Mb)/+)的3.0-Mb缺失。通过视觉诱发电位、昼夜行为节律和一系列行为测试，如运动活动测量、脉冲前抑制、恐惧条件记忆和视觉辨别学习，对成年雄性突变体的行为学和生理学表型进行了综合评价。结果显示，Del(3.0Mb)/+小鼠听觉前脉冲抑制减少，线索依赖恐惧记忆减弱，这与已有的22q11.2DS模型的表型一致。此外，DEL(3.0Mb)/+小鼠表现出精神分裂症患者常见的早期视觉加工障碍。与此同时，与现有模型不同的是，Del(3.0Mb)/+小鼠在几项行为测试中表现出活动不足，这可能反映了22q11.2DS患者的疲劳性。最后，与野生型小鼠相比，Del(3.0Mb)/+小鼠对实验时差的适应速度更快。我们的结果支持Del(3.0Mb)/+小鼠作为精神分裂症动物模型的有效性，并表明我们的小鼠模型是了解精神分裂症和其他与22q11.2DS相关的精神障碍的致病机制的有用资源。
The 22q11.2 deletion syndrome (22q11.2DS) is associated with an increased risk for psychiatric disorders. Although most of the 22q11.2DS patients have a 3.0-Mb deletion, existing mouse models only mimic a minor mutation of 22q11.2DS, a 1.5-Mb deletion. The role of the genes existing outside the 1.5-Mb deletion in psychiatric symptoms of 22q11.2DS is unclear. In this study, we generated a mouse model that reproduced the 3.0-Mb deletion of the 22q11.2DS (Del(3.0Mb)/+) using the CRISPR/Cas9 system. Ethological and physiological phenotypes of adult male mutants were comprehensively evaluated by visual-evoked potentials, circadian behavioral rhythm, and a series of behavioral tests, such as measurement of locomotor activity, prepulse inhibition, fear-conditioning memory, and visual discrimination learning. As a result, Del(3.0Mb)/+mice showed reduction of auditory prepulse inhibition and attenuated cue-dependent fear memory, which is consistent with the phenotypes of existing 22q11.2DS models. In addition, Del(3.0Mb)/+mice displayed an impaired early visual processing that is commonly seen in patients with schizophrenia. Meanwhile, unlike the existing models, Del(3.0Mb)/+mice exhibited hypoactivity over several behavioral tests, possibly reflecting the fatigability of 22q11.2DS patients. Lastly, Del(3.0Mb)/+mice displayed a faster adaptation to experimental jet lag as compared with wild-type mice. Our results support the validity of Del(3.0Mb)/+mice as a schizophrenia animal model and suggest that our mouse model is a useful resource to understand pathogenic mechanisms of schizophrenia and other psychiatric disorders associated with 22q11.2DS.