Dataset Information

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.

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.

SUBMITTER: Saito R

PROVIDER: S-EPMC7026107 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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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.

Saito Ryo R Koebis Michinori M Nagai Taku T Shimizu Kimiko K Liao Jingzhu J Wulaer Bolati B Sugaya Yuki Y Nagahama Kenichiro K Uesaka Naofumi N Kushima Itaru I Mori Daisuke D Maruyama Kazuaki K Nakao Kazuki K Kurihara Hiroki H Yamada Kiyofumi K Kano Masanobu M Fukada Yoshitaka Y Ozaki Norio N Aiba Atsu A

Translational psychiatry 20200205 1

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 syste ...[more]

PMID: 32066675

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Project description:Background22q11.2 deletion syndrome (22qDS) manifests with myriad symptoms, including multiple neuropsychiatric disorders. Complications associated with the polygenic haploinsufficiency make 22qDS symptoms particularly difficult to manage with traditional therapeutic approaches. However, the varying mechanistic consequences often culminate to generate inappropriate regulation of neuronal circuit activity. We explored whether managing this aberrant activity in adults could be a therapeutically beneficial strategy.MethodsTo assess and dissect hippocampal circuit function, we performed functional imaging in acute slices and targeted eloquent circuits (specific subcircuits tied to specific behavioral tasks) to provide relevant behavioral outputs. For example, the ventral and dorsal CA1 regions critically support social and spatial discrimination, respectively. We focally introduced chemogenetic constructs in 34 control and 24 22qDS model mice via adeno-associated viral vectors, driven by excitatory neuron-specific promoter elements, to manipulate circuit recruitment in an on-demand fashion.Results22qDS model mice exhibited CA1 excitatory ensemble hyperexcitability and concomitant behavioral deficits in both social and spatial memory. Remarkably, acute chemogenetic inhibition of pyramidal cells successfully corrected memory deficits and did so in a regionally specific manner: ventrally targeted constructs rescued only social behavior, while those expressed dorsally selectively affected spatial memory. Additionally, manipulating activity in control mice could recapitulate the memory deficits in a regionally specific manner.ConclusionsThese data suggest that retuning activity dysregulation can rescue function in disease-altered circuits, even in the face of a polygenetic haploinsufficiency with a strong developmental component. Targeting circuit excitability in a focal, modular manner may prove to be an effective therapeutic for treatment-resistant symptoms of mental illness.

Dataset Information

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.

Publications

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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