CRISPR/Cas9-engineered Gad1 elimination in rats leads to complex behavioral changes: implications for schizophrenia
Abstract GABAergic dysfunctions have been implicated in the pathogenesis of schizophrenia, especially the associated cognitive impairments. The GABA synthetic enzyme glutamate decarboxylase 67-kDa isoform (GAD67) encoded by the GAD1 gene is downregulated in the brains of patients with schizophrenia....
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2020-12-01
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Series: | Translational Psychiatry |
Online Access: | https://doi.org/10.1038/s41398-020-01108-6 |
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doaj-2dbb2490b6c040e7aed36c58c57cba202020-12-13T12:40:35ZengNature Publishing GroupTranslational Psychiatry2158-31882020-12-0110111310.1038/s41398-020-01108-6CRISPR/Cas9-engineered Gad1 elimination in rats leads to complex behavioral changes: implications for schizophreniaKazuyuki Fujihara0Kazuo Yamada1Yukio Ichitani2Toshikazu Kakizaki3Weiru Jiang4Shigeo Miyata5Takashi Suto6Daiki Kato7Shigeru Saito8Masahiko Watanabe9Yuki Kajita10Tomokazu Ohshiro11Hajime Mushiake12Yoshiki Miyasaka13Tomoji Mashimo14Hiroki Yasuda15Yuchio Yanagawa16Department of Genetic and Behavioral Neuroscience, Gunma University Graduate School of MedicineInstitute of Psychology and Behavioral Neuroscience, University of TsukubaInstitute of Psychology and Behavioral Neuroscience, University of TsukubaDepartment of Genetic and Behavioral Neuroscience, Gunma University Graduate School of MedicineDepartment of Genetic and Behavioral Neuroscience, Gunma University Graduate School of MedicineDepartment of Genetic and Behavioral Neuroscience, Gunma University Graduate School of MedicineDepartment of Anesthesiology, Gunma University Graduate School of MedicineDepartment of Anesthesiology, Gunma University Graduate School of MedicineDepartment of Anesthesiology, Gunma University Graduate School of MedicineDepartment of Anatomy, Faculty of Medicine, Hokkaido UniversityDepartment of Physiology, Graduate School of Medicine, Tohoku UniversityDepartment of Physiology, Graduate School of Medicine, Tohoku UniversityDepartment of Physiology, Graduate School of Medicine, Tohoku UniversityInstitute of Experimental Animal Sciences, Graduate School of Medicine, Osaka UniversityInstitute of Experimental Animal Sciences, Graduate School of Medicine, Osaka UniversityDivision of Physiology, Faculty of Medicine, Saga UniversityDepartment of Genetic and Behavioral Neuroscience, Gunma University Graduate School of MedicineAbstract GABAergic dysfunctions have been implicated in the pathogenesis of schizophrenia, especially the associated cognitive impairments. The GABA synthetic enzyme glutamate decarboxylase 67-kDa isoform (GAD67) encoded by the GAD1 gene is downregulated in the brains of patients with schizophrenia. Furthermore, a patient with schizophrenia harboring a homozygous mutation of GAD1 has recently been discovered. However, it remains unclear whether loss of function of GAD1 leads to the symptoms observed in schizophrenia, including cognitive impairment. One of the obstacles faced in experimental studies to address this issue is the perinatal lethality of Gad1 knockout (KO) mice, which precluded characterization at the adult stage. In the present study, we successfully generated Gad1 KO rats using CRISPR/Cas9 genome editing technology. Surprisingly, 33% of Gad1 KO rats survived to adulthood and could be subjected to further characterization. The GABA concentration in the Gad1 KO cerebrum was reduced to ~52% of the level in wild-type rats. Gad1 KO rats exhibited impairments in both spatial reference and working memory without affecting adult neurogenesis in the hippocampus. In addition, Gad1 KO rats showed a wide range of behavioral alterations, such as enhanced sensitivity to an NMDA receptor antagonist, hypoactivity in a novel environment, and decreased preference for social novelty. Taken together, the results suggest that Gad1 KO rats could provide a novel model covering not only cognitive deficits but also other aspects of the disorder. Furthermore, the present study teaches an important lesson: differences between species should be considered when developing animal models of human diseases.https://doi.org/10.1038/s41398-020-01108-6 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Kazuyuki Fujihara Kazuo Yamada Yukio Ichitani Toshikazu Kakizaki Weiru Jiang Shigeo Miyata Takashi Suto Daiki Kato Shigeru Saito Masahiko Watanabe Yuki Kajita Tomokazu Ohshiro Hajime Mushiake Yoshiki Miyasaka Tomoji Mashimo Hiroki Yasuda Yuchio Yanagawa |
spellingShingle |
Kazuyuki Fujihara Kazuo Yamada Yukio Ichitani Toshikazu Kakizaki Weiru Jiang Shigeo Miyata Takashi Suto Daiki Kato Shigeru Saito Masahiko Watanabe Yuki Kajita Tomokazu Ohshiro Hajime Mushiake Yoshiki Miyasaka Tomoji Mashimo Hiroki Yasuda Yuchio Yanagawa CRISPR/Cas9-engineered Gad1 elimination in rats leads to complex behavioral changes: implications for schizophrenia Translational Psychiatry |
author_facet |
Kazuyuki Fujihara Kazuo Yamada Yukio Ichitani Toshikazu Kakizaki Weiru Jiang Shigeo Miyata Takashi Suto Daiki Kato Shigeru Saito Masahiko Watanabe Yuki Kajita Tomokazu Ohshiro Hajime Mushiake Yoshiki Miyasaka Tomoji Mashimo Hiroki Yasuda Yuchio Yanagawa |
author_sort |
Kazuyuki Fujihara |
title |
CRISPR/Cas9-engineered Gad1 elimination in rats leads to complex behavioral changes: implications for schizophrenia |
title_short |
CRISPR/Cas9-engineered Gad1 elimination in rats leads to complex behavioral changes: implications for schizophrenia |
title_full |
CRISPR/Cas9-engineered Gad1 elimination in rats leads to complex behavioral changes: implications for schizophrenia |
title_fullStr |
CRISPR/Cas9-engineered Gad1 elimination in rats leads to complex behavioral changes: implications for schizophrenia |
title_full_unstemmed |
CRISPR/Cas9-engineered Gad1 elimination in rats leads to complex behavioral changes: implications for schizophrenia |
title_sort |
crispr/cas9-engineered gad1 elimination in rats leads to complex behavioral changes: implications for schizophrenia |
publisher |
Nature Publishing Group |
series |
Translational Psychiatry |
issn |
2158-3188 |
publishDate |
2020-12-01 |
description |
Abstract GABAergic dysfunctions have been implicated in the pathogenesis of schizophrenia, especially the associated cognitive impairments. The GABA synthetic enzyme glutamate decarboxylase 67-kDa isoform (GAD67) encoded by the GAD1 gene is downregulated in the brains of patients with schizophrenia. Furthermore, a patient with schizophrenia harboring a homozygous mutation of GAD1 has recently been discovered. However, it remains unclear whether loss of function of GAD1 leads to the symptoms observed in schizophrenia, including cognitive impairment. One of the obstacles faced in experimental studies to address this issue is the perinatal lethality of Gad1 knockout (KO) mice, which precluded characterization at the adult stage. In the present study, we successfully generated Gad1 KO rats using CRISPR/Cas9 genome editing technology. Surprisingly, 33% of Gad1 KO rats survived to adulthood and could be subjected to further characterization. The GABA concentration in the Gad1 KO cerebrum was reduced to ~52% of the level in wild-type rats. Gad1 KO rats exhibited impairments in both spatial reference and working memory without affecting adult neurogenesis in the hippocampus. In addition, Gad1 KO rats showed a wide range of behavioral alterations, such as enhanced sensitivity to an NMDA receptor antagonist, hypoactivity in a novel environment, and decreased preference for social novelty. Taken together, the results suggest that Gad1 KO rats could provide a novel model covering not only cognitive deficits but also other aspects of the disorder. Furthermore, the present study teaches an important lesson: differences between species should be considered when developing animal models of human diseases. |
url |
https://doi.org/10.1038/s41398-020-01108-6 |
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