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

Ryo Saito,Bolati Wulaer,Taku Nagai,Kimiko Shimizu,Kazuaki Maruyama,Yoshitaka Fukada,Kenichiro Nagahama,Atsu Aiba,Jingzhu Liao,Norio Ozaki,Michinori Koebis,Yuki Sugaya,Masanobu Kano,Kazuki Nakao,Kiyofumi Yamada,Naofumi Uesaka,Daisuke Mori,Itaru Kushima,Hiroki Kurihara

doi:10.1038/s41398-020-0723-z

Ryo Saito, Bolati Wulaer + Show 17 more

Open Access

https://doi.org/10.1038/s41398-020-0723-z

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Abstract

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.

Highlights

The 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion syndrome in humans, and estimated to affect up to 1 in 4000 live births[1]
Generation of Del(3.0 Mb)/ + mice To generate Del(3.0 Mb)/ + mice, we carried out CRISPR/Cas9-mediated genome editing by injected four single-guide RNAs and a single-stranded oligodeoxyribonucleotide into C57BL/6N mouse zygotes, as previously described[21]
To generate a mouse with a deletion that corresponds to the most common 3.0-Mb deletion in 22q11.2DS patients, we introduced the deletion between Pi4ka and Hira genes on mouse chromosome 16 using CRISPR/Cas[9] system

Summary

Introduction

The 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion syndrome in humans, and estimated to affect up to 1 in 4000 live births[1]. Individuals with this syndrome display multiple physical abnormalities; cardiac malformation is the most frequent symptom affecting ~80% of patients, followed by less frequent symptoms, such as velopharyngeal insufficiency, hypocalcemia, thymus hypoplasia, and immune deficiency. 22q11.2DS is known to increase the risk of developing a variety of psychiatric and developmental disorders, including schizophrenia, intellectual disability, autism spectrum disorder, attention deficit hyperactivity disorder (ADHD), early-onset Parkinson’s disease, and sleep behavior disorder[2,3,4,5,6]. Studying 22q11.2DS will shed light on the pathogenesis of schizophrenia

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