TY - JOUR
T1 - Generation and analysis of novel Reln-deleted mouse model corresponding to exonic Reln deletion in schizophrenia
AU - Sawahata, Masahito
AU - Mori, Daisuke
AU - Arioka, Yuko
AU - Kubo, Hisako
AU - Kushima, Itaru
AU - Kitagawa, Kanako
AU - Sobue, Akira
AU - Shishido, Emiko
AU - Sekiguchi, Mariko
AU - Kodama, Akiko
AU - Ikeda, Ryosuke
AU - Aleksic, Branko
AU - Kimura, Hiroki
AU - Ishizuka, Kanako
AU - Nagai, Taku
AU - Kaibuchi, Kozo
AU - Nabeshima, Toshitaka
AU - Yamada, Kiyofumi
AU - Ozaki, Norio
N1 - Funding Information:
We thank the Division for Research of Laboratory Animals; the Division for Medical Research Engineering for animal care and use; and the Division of Psychiatry and Brain and Mind Research Center. We also thank Enago ( www.enago.jp ) for the English‐language review. This study was supported by AMED under Grants JP19dm0107087, JP19dm0207005h, JP19ak0101113, JP19dk0307081; Japan Society for the Promotion of Science (JSPS) KAKENHI Grants 23110506, 23700443, 25110715, 25460284, 17H04252, and 18H04040; the Private University Research Branding Project from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT). Innovative Areas ‘Glial assembly: a new regulatory machinery of brain function and disorders’; Nagoya University Hospital Funding for Clinical Research; The NAKAJIMA Foundation, and the SENSHIN Medical Research Foundation.
Funding Information:
We thank the Division for Research of Laboratory Animals; the Division for Medical Research Engineering for animal care and use; and the Division of Psychiatry and Brain and Mind Research Center. We also thank Enago (www.enago.jp) for the English-language review. This study was supported by AMED under Grants JP19dm0107087, JP19dm0207005h, JP19ak0101113, JP19dk0307081; Japan Society for the Promotion of Science (JSPS) KAKENHI Grants 23110506, 23700443, 25110715, 25460284, 17H04252, and 18H04040; the Private University Research Branding Project from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT). Innovative Areas ‘Glial assembly: a new regulatory machinery of brain function and disorders’; Nagoya University Hospital Funding for Clinical Research; The NAKAJIMA Foundation, and the SENSHIN Medical Research Foundation.
Publisher Copyright:
© 2020 The Authors Psychiatry and Clinical Neurosciences published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society of Psychiatry and Neurology
PY - 2020/5/1
Y1 - 2020/5/1
N2 - Aim: A Japanese individual with schizophrenia harboring a novel exonic deletion in RELN was recently identified by genome-wide copy-number variation analysis. Thus, the present study aimed to generate and analyze a model mouse to clarify whether Reln deficiency is associated with the pathogenesis of schizophrenia. Methods: A mouse line with a novel RELN exonic deletion (Reln-del) was established using the CRISPR/Cas9 method to elucidate the underlying molecular mechanism. Subsequently, general behavioral tests and histopathological examinations of the model mice were conducted and phenotypic analysis of the cerebellar granule cell migration was performed. Results: The phenotype of homozygous Reln-del mice was similar to that of reeler mice with cerebellar atrophy, dysplasia of the cerebral layers, and abrogated protein levels of cerebral reelin. The expression of reelin in heterozygous Reln-del mice was approximately half of that in wild-type mice. Conversely, behavioral analyses in heterozygous Reln-del mice without cerebellar atrophy or dysplasia showed abnormal social novelty in the three-chamber social interaction test. In vitro reaggregation formation and neuronal migration were severely altered in the cerebellar cultures of homozygous Reln-del mice. Conclusion: The present results in novel Reln-del mice modeled after our patient with a novel exonic deletion in RELN are expected to contribute to the development of reelin-based therapies for schizophrenia.
AB - Aim: A Japanese individual with schizophrenia harboring a novel exonic deletion in RELN was recently identified by genome-wide copy-number variation analysis. Thus, the present study aimed to generate and analyze a model mouse to clarify whether Reln deficiency is associated with the pathogenesis of schizophrenia. Methods: A mouse line with a novel RELN exonic deletion (Reln-del) was established using the CRISPR/Cas9 method to elucidate the underlying molecular mechanism. Subsequently, general behavioral tests and histopathological examinations of the model mice were conducted and phenotypic analysis of the cerebellar granule cell migration was performed. Results: The phenotype of homozygous Reln-del mice was similar to that of reeler mice with cerebellar atrophy, dysplasia of the cerebral layers, and abrogated protein levels of cerebral reelin. The expression of reelin in heterozygous Reln-del mice was approximately half of that in wild-type mice. Conversely, behavioral analyses in heterozygous Reln-del mice without cerebellar atrophy or dysplasia showed abnormal social novelty in the three-chamber social interaction test. In vitro reaggregation formation and neuronal migration were severely altered in the cerebellar cultures of homozygous Reln-del mice. Conclusion: The present results in novel Reln-del mice modeled after our patient with a novel exonic deletion in RELN are expected to contribute to the development of reelin-based therapies for schizophrenia.
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U2 - 10.1111/pcn.12993
DO - 10.1111/pcn.12993
M3 - Article
C2 - 32065683
AN - SCOPUS:85080966724
SN - 1323-1316
VL - 74
SP - 318
EP - 327
JO - Psychiatry and Clinical Neurosciences
JF - Psychiatry and Clinical Neurosciences
IS - 5
ER -