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.,Translational Psychiatry

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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.
Translational Psychiatry ( IF 5.8 ) Pub Date : 2020-02-05 , DOI: 10.1038/s41398-020-0723-z
Ryo Saito _{1,

2} , Michinori Koebis ₁ , Taku Nagai ₃ , Kimiko Shimizu ₂ , Jingzhu Liao ₃ , Bolati Wulaer ₃ , Yuki Sugaya _{4,

5} , Kenichiro Nagahama _{4,

5} , Naofumi Uesaka _{4,

5} , Itaru Kushima _{6,

7} , Daisuke Mori ₆ , Kazuaki Maruyama ₈ , Kazuki Nakao ₁ , Hiroki Kurihara ₈ , Kiyofumi Yamada ₃ , Masanobu Kano _{4,

5} , Yoshitaka Fukada ₂ , Norio Ozaki ₆ , Atsu Aiba _{1,

2}

Affiliation

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(3.0 Mb)/ +) 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(3.0 Mb)/ + 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(3.0 Mb)/ + mice displayed an impaired early visual processing that is commonly seen in patients with schizophrenia. Meanwhile, unlike the existing models, Del(3.0 Mb)/ + mice exhibited hypoactivity over several behavioral tests, possibly reflecting the fatigability of 22q11.2DS patients. Lastly, Del(3.0 Mb)/ + mice displayed a faster adaptation to experimental jet lag as compared with wild-type mice. Our results support the validity of Del(3.0 Mb)/ + 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.

中文翻译：

22q11.2 缺失综合征新型小鼠模型的综合分析：人类 22q11.2 基因座最常见的 3.0-Mb 缺失模型。

22q11.2 缺失综合征 (22q11.2DS) 与精神疾病风险增加有关。尽管大多数 22q11.2DS 患者有 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。在这项研究中，我们使用 CRISPR/Cas9 系统生成了一个小鼠模型，该模型再现了 22q11.2DS (Del(3.0 Mb)/ +) 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、前脉冲抑制、恐惧条件记忆和视觉辨别学习等，对成年男性突变体的行为学和生理表型进行了综合评估。因此，德尔（3。0 Mb)/ + 小鼠表现出听觉前脉冲抑制减少和线索依赖性恐惧记忆减弱，这与现有 22q11.2DS 模型的表型一致。此外，Del(3.0 Mb)/ + 小鼠表现出早期视觉处理受损，这在精神分裂症患者中很常见。同时，与现有模型不同，Del(3.0 Mb)/ + 小鼠在多次行为测试中表现出低活性，可能反映了 22q11.2DS 患者的易疲劳性。最后，与野生型小鼠相比，Del(3.0 Mb)/ + 小鼠对实验时差的适应更快。我们的结果支持 Del(3.0 Mb)/ + 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 相关的精神疾病的发病机制的有用资源。

更新日期：2020-02-06

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