Deficiency of schnurri-2, an MHC enhancer binding protein, induces mild chronic inflammation in the brain and confers molecular, neuronal, and behavioral phenotypes related to schizophrenia

Keizo Takao, Katsunori Kobayashi, Hideo Hagihara, Koji Ohira, Hirotaka Shoji, Satoko Takai, Hisatsugu Koshimizu, Juzoh Umemori, Keiko Toyama, Hironori K. Nakamura, Mahomi Kuroiwa, Jun Maeda, Kimie Atsuzawa, Kayoko Esaki, Shun Yamaguchi, Shigeki Furuya, Tsuyoshi Takagi, Noah M. Walton, Nobuhiro Hayashi, Hidenori Suzuki & 7 others Makoto Higuchi, Nobuteru Usuda, Tetsuya Suhara, Akinori Nishi, Mitsuyuki Matsumoto, Shunsuke Ishii, Tsuyoshi Miyakawa

Research output: Contribution to journalArticle

82 Citations (Scopus)

Abstract

Schnurri-2 (Shn-2), an nuclear factor-κB site-binding protein, tightly binds to the enhancers of major histocompatibility complex class I genes and inflammatory cytokines, which have been shown to harbor common variant single-nucleotide polymorphisms associated with schizophrenia. Although genes related to immunity are implicated in schizophrenia, there has been no study showing that their mutation or knockout (KO) results in schizophrenia. Here, we show that Shn-2 KO mice have behavioral abnormalities that resemble those of schizophrenics. The mutant brain demonstrated multiple schizophrenia-related phenotypes, including transcriptome/proteome changes similar to those of postmortem schizophrenia patients, decreased parvalbumin and GAD67 levels, increased theta power on electroencephalograms, and a thinner cortex. Dentate gyrus granule cells failed to mature in mutants, a previously proposed endophenotype of schizophrenia. Shn-2 KO mice also exhibited mild chronic inflammation of the brain, as evidenced by increased inflammation markers (including GFAP and NADH/NADPH oxidase p22 phox), and genome-wide gene expression patterns similar to various inflammatory conditions. Chronic administration of anti-inflammatory drugs reduced hippocampal GFAP expression, and reversed deficits in working memory and nest-building behaviors in Shn-2 KO mice. These results suggest that genetically induced changes in immune system can be a predisposing factor in schizophrenia.

Original languageEnglish
Pages (from-to)1409-1425
Number of pages17
JournalNeuropsychopharmacology
Volume38
Issue number8
DOIs
Publication statusPublished - 01-07-2013

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Encephalitis
Schizophrenia
Carrier Proteins
Phenotype
Knockout Mice
Endophenotypes
MHC Class I Genes
Parvalbumins
NADPH Oxidase
Dentate Gyrus
Proteome
Major Histocompatibility Complex
Short-Term Memory
Transcriptome
Causality
Single Nucleotide Polymorphism
Electroencephalography
Immune System
Immunity
Anti-Inflammatory Agents

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Psychiatry and Mental health

Cite this

Takao, Keizo ; Kobayashi, Katsunori ; Hagihara, Hideo ; Ohira, Koji ; Shoji, Hirotaka ; Takai, Satoko ; Koshimizu, Hisatsugu ; Umemori, Juzoh ; Toyama, Keiko ; Nakamura, Hironori K. ; Kuroiwa, Mahomi ; Maeda, Jun ; Atsuzawa, Kimie ; Esaki, Kayoko ; Yamaguchi, Shun ; Furuya, Shigeki ; Takagi, Tsuyoshi ; Walton, Noah M. ; Hayashi, Nobuhiro ; Suzuki, Hidenori ; Higuchi, Makoto ; Usuda, Nobuteru ; Suhara, Tetsuya ; Nishi, Akinori ; Matsumoto, Mitsuyuki ; Ishii, Shunsuke ; Miyakawa, Tsuyoshi. / Deficiency of schnurri-2, an MHC enhancer binding protein, induces mild chronic inflammation in the brain and confers molecular, neuronal, and behavioral phenotypes related to schizophrenia. In: Neuropsychopharmacology. 2013 ; Vol. 38, No. 8. pp. 1409-1425.
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abstract = "Schnurri-2 (Shn-2), an nuclear factor-κB site-binding protein, tightly binds to the enhancers of major histocompatibility complex class I genes and inflammatory cytokines, which have been shown to harbor common variant single-nucleotide polymorphisms associated with schizophrenia. Although genes related to immunity are implicated in schizophrenia, there has been no study showing that their mutation or knockout (KO) results in schizophrenia. Here, we show that Shn-2 KO mice have behavioral abnormalities that resemble those of schizophrenics. The mutant brain demonstrated multiple schizophrenia-related phenotypes, including transcriptome/proteome changes similar to those of postmortem schizophrenia patients, decreased parvalbumin and GAD67 levels, increased theta power on electroencephalograms, and a thinner cortex. Dentate gyrus granule cells failed to mature in mutants, a previously proposed endophenotype of schizophrenia. Shn-2 KO mice also exhibited mild chronic inflammation of the brain, as evidenced by increased inflammation markers (including GFAP and NADH/NADPH oxidase p22 phox), and genome-wide gene expression patterns similar to various inflammatory conditions. Chronic administration of anti-inflammatory drugs reduced hippocampal GFAP expression, and reversed deficits in working memory and nest-building behaviors in Shn-2 KO mice. These results suggest that genetically induced changes in immune system can be a predisposing factor in schizophrenia.",
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Takao, K, Kobayashi, K, Hagihara, H, Ohira, K, Shoji, H, Takai, S, Koshimizu, H, Umemori, J, Toyama, K, Nakamura, HK, Kuroiwa, M, Maeda, J, Atsuzawa, K, Esaki, K, Yamaguchi, S, Furuya, S, Takagi, T, Walton, NM, Hayashi, N, Suzuki, H, Higuchi, M, Usuda, N, Suhara, T, Nishi, A, Matsumoto, M, Ishii, S & Miyakawa, T 2013, 'Deficiency of schnurri-2, an MHC enhancer binding protein, induces mild chronic inflammation in the brain and confers molecular, neuronal, and behavioral phenotypes related to schizophrenia', Neuropsychopharmacology, vol. 38, no. 8, pp. 1409-1425. https://doi.org/10.1038/npp.2013.38

Deficiency of schnurri-2, an MHC enhancer binding protein, induces mild chronic inflammation in the brain and confers molecular, neuronal, and behavioral phenotypes related to schizophrenia. / Takao, Keizo; Kobayashi, Katsunori; Hagihara, Hideo; Ohira, Koji; Shoji, Hirotaka; Takai, Satoko; Koshimizu, Hisatsugu; Umemori, Juzoh; Toyama, Keiko; Nakamura, Hironori K.; Kuroiwa, Mahomi; Maeda, Jun; Atsuzawa, Kimie; Esaki, Kayoko; Yamaguchi, Shun; Furuya, Shigeki; Takagi, Tsuyoshi; Walton, Noah M.; Hayashi, Nobuhiro; Suzuki, Hidenori; Higuchi, Makoto; Usuda, Nobuteru; Suhara, Tetsuya; Nishi, Akinori; Matsumoto, Mitsuyuki; Ishii, Shunsuke; Miyakawa, Tsuyoshi.

In: Neuropsychopharmacology, Vol. 38, No. 8, 01.07.2013, p. 1409-1425.

Research output: Contribution to journalArticle

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T1 - Deficiency of schnurri-2, an MHC enhancer binding protein, induces mild chronic inflammation in the brain and confers molecular, neuronal, and behavioral phenotypes related to schizophrenia

AU - Takao, Keizo

AU - Kobayashi, Katsunori

AU - Hagihara, Hideo

AU - Ohira, Koji

AU - Shoji, Hirotaka

AU - Takai, Satoko

AU - Koshimizu, Hisatsugu

AU - Umemori, Juzoh

AU - Toyama, Keiko

AU - Nakamura, Hironori K.

AU - Kuroiwa, Mahomi

AU - Maeda, Jun

AU - Atsuzawa, Kimie

AU - Esaki, Kayoko

AU - Yamaguchi, Shun

AU - Furuya, Shigeki

AU - Takagi, Tsuyoshi

AU - Walton, Noah M.

AU - Hayashi, Nobuhiro

AU - Suzuki, Hidenori

AU - Higuchi, Makoto

AU - Usuda, Nobuteru

AU - Suhara, Tetsuya

AU - Nishi, Akinori

AU - Matsumoto, Mitsuyuki

AU - Ishii, Shunsuke

AU - Miyakawa, Tsuyoshi

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