論文

国際誌
2020年12月8日

CRISPR/Cas9-engineered Gad1 elimination in rats leads to complex behavioral changes: implications for schizophrenia.

Translational psychiatry
  • 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
  • 全て表示

10
1
開始ページ
426
終了ページ
426
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1038/s41398-020-01108-6

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.

リンク情報
DOI
https://doi.org/10.1038/s41398-020-01108-6
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/33293518
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723991
ID情報
  • DOI : 10.1038/s41398-020-01108-6
  • PubMed ID : 33293518
  • PubMed Central 記事ID : PMC7723991

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