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Elevation of EGR1/zif268, a Neural Activity Marker, in the Auditory Cortex of Patients with Schizophrenia and its Animal Model

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Abstract

The family of epidermal growth factor (EGF) including neuregulin-1 are implicated in the neuropathology of schizophrenia. We established a rat model of schizophrenia by exposing perinatal rats to EGF and reported that the auditory pathophysiological traits of this model such as prepulse inhibition, auditory steady-state response, and mismatch negativity are relevant to those of schizophrenia. We assessed the activation status of the auditory cortex in this model, as well as that in patients with schizophrenia, by monitoring the three neural activity-induced proteins: EGR1 (zif268), c-fos, and Arc. Among the activity markers, protein levels of EGR1 were significantly higher at the adult stage in EGF model rats than those in control rats. The group difference was observed despite an EGF model rat and a control rat being housed together, ruling out the contribution of rat vocalization effects. These changes in EGR1 levels were seen to be specific to the auditory cortex of this model. The increase in EGR1 levels were detectable at the juvenile stage and continued until old ages but displayed a peak immediately after puberty, whereas c-fos and Arc levels were nearly indistinguishable between groups at all ages with an exception of Arc decrease at the juvenile stage. A similar increase in EGR1 levels was observed in the postmortem superior temporal cortex of patients with schizophrenia. The commonality of the EGR1 increase indicates that the EGR1 elevation in the auditory cortex might be one of the molecular signatures of this animal model and schizophrenia associating with hallucination.

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Acknowledgements

The authors would like to thank Dr. Shunsuke Hasegawa for technical assistance with the experiments. This research was supported by Grant-in-Aid for Scientific Research on Innovative Areas (18H05429, H.N.) and for Challenging Research (21K18242, H.N.), the Japan Agency for Medical Research and Development (AMED, JP21wm0425019, A.K.), the Strategic Research Program for Brain Sciences from AMED (JP21wm0425019, H.Y. and JP21dm0207074, Y.K.), the Grant-in-Aid for Scientific Research on Innovative Areas from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (JP21H00180, Y.K.), the Grants-in-Aid for Scientific Research (C) (19K08053, Y.K.), the Ministry of Education, Culture, Sports, Science, and Technology Supported Program for the Strategic Research Foundation at Private Universities (S1311017, RK-M), and the Collaborative Research Project of Brain Research Institute, Niigata University (201917, Y.K.).

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Authors and Affiliations

  1. Department of Molecular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan

    Yuriko Iwakura, Hidekazu Sotoyama & Hiroyuki Nawa

  2. Department of Brain Tumor Biology, Brain Research Institute, Niigata University, 1-757 Asahimachi-Dori, Chuo-ku, Niigata City, Niigata, 951-8585, Japan

    Yuriko Iwakura

  3. NODAI Genome Research Center, Tokyo University of Agriculture, Tokyo, Japan

    Ryoka Kawahara-Miki

  4. Graduate School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan

    Satoshi Kida

  5. Department of Bioscience, Faculty of Life Science, Tokyo University of Agriculture, Tokyo, Japan

    Satoshi Kida

  6. Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan

    Ramil Gabdulkhaev, Hitoshi Takahashi & Akiyoshi Kakita

  7. Department of Neuropsychiatry, Fukushima Medical University School of Medicine, Fukushima, Japan

    Yasuto Kunii, Mizuki Hino, Atsuko Nagaoka, Ryuta Izumi, Risa Shishido & Hirooki Yabe

  8. Department of Disaster Psychiatry, International Research Institute of Disaster Science, Tohoku University, Sendai, Japan

    Yasuto Kunii & Mizuki Hino

  9. Department of Psychiatry, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan

    Toshiyuki Someya

  10. Department of Physiological Sciences, School of Pharmaceutical Sciences, Wakayama Medical University, Wakayama, Japan

    Hiroyuki Nawa

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  1. Yuriko Iwakura
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Contributions

All authors contributed to the study conception and design. YI, SK, TS and HN contributed to the study conception and design. YI, RK-M, and HS performed experiments. Materials were prepared or collected by RG, HT, YK, MH, AN, RI, RS, HY, AK. The first draft of the manuscript was written by YI and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Yuriko Iwakura.

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Iwakura, Y., Kawahara-Miki, R., Kida, S. et al. Elevation of EGR1/zif268, a Neural Activity Marker, in the Auditory Cortex of Patients with Schizophrenia and its Animal Model. Neurochem Res 47, 2715–2727 (2022). https://doi.org/10.1007/s11064-022-03599-9

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  • DOI: https://doi.org/10.1007/s11064-022-03599-9

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