EMBO Molecular Medicine (Oct 2019)
Excess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology
- Masayuki Ide,
- Tetsuo Ohnishi,
- Manabu Toyoshima,
- Shabeesh Balan,
- Motoko Maekawa,
- Chie Shimamoto‐Mitsuyama,
- Yoshimi Iwayama,
- Hisako Ohba,
- Akiko Watanabe,
- Takashi Ishii,
- Norihiro Shibuya,
- Yuka Kimura,
- Yasuko Hisano,
- Yui Murata,
- Tomonori Hara,
- Momo Morikawa,
- Kenji Hashimoto,
- Yayoi Nozaki,
- Tomoko Toyota,
- Yuina Wada,
- Yosuke Tanaka,
- Tadafumi Kato,
- Akinori Nishi,
- Shigeyoshi Fujisawa,
- Hideyuki Okano,
- Masanari Itokawa,
- Nobutaka Hirokawa,
- Yasuto Kunii,
- Akiyoshi Kakita,
- Hirooki Yabe,
- Kazuya Iwamoto,
- Kohji Meno,
- Takuya Katagiri,
- Brian Dean,
- Kazuhiko Uchida,
- Hideo Kimura,
- Takeo Yoshikawa
Affiliations
- Masayuki Ide
- Laboratory of Molecular Psychiatry, RIKEN Center for Brain Science
- Tetsuo Ohnishi
- Laboratory of Molecular Psychiatry, RIKEN Center for Brain Science
- Manabu Toyoshima
- Laboratory of Molecular Psychiatry, RIKEN Center for Brain Science
- Shabeesh Balan
- Laboratory of Molecular Psychiatry, RIKEN Center for Brain Science
- Motoko Maekawa
- Laboratory of Molecular Psychiatry, RIKEN Center for Brain Science
- Chie Shimamoto‐Mitsuyama
- Laboratory of Molecular Psychiatry, RIKEN Center for Brain Science
- Yoshimi Iwayama
- Laboratory of Molecular Psychiatry, RIKEN Center for Brain Science
- Hisako Ohba
- Laboratory of Molecular Psychiatry, RIKEN Center for Brain Science
- Akiko Watanabe
- Laboratory of Molecular Psychiatry, RIKEN Center for Brain Science
- Takashi Ishii
- Research& Development Department, MCBI Inc
- Norihiro Shibuya
- Department of Pharmacology, Sanyo‐Onoda City University
- Yuka Kimura
- Department of Pharmacology, Sanyo‐Onoda City University
- Yasuko Hisano
- Laboratory of Molecular Psychiatry, RIKEN Center for Brain Science
- Yui Murata
- Department of Molecular Brain Science, Graduate School of Medical Sciences, Kumamoto University
- Tomonori Hara
- Laboratory of Molecular Psychiatry, RIKEN Center for Brain Science
- Momo Morikawa
- Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo
- Kenji Hashimoto
- Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health
- Yayoi Nozaki
- Laboratory of Molecular Psychiatry, RIKEN Center for Brain Science
- Tomoko Toyota
- Laboratory of Molecular Psychiatry, RIKEN Center for Brain Science
- Yuina Wada
- Laboratory of Molecular Psychiatry, RIKEN Center for Brain Science
- Yosuke Tanaka
- Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo
- Tadafumi Kato
- Laboratory for Molecular Dynamics of Mental Disorders, RIKEN Center for Brain Science
- Akinori Nishi
- Department of Pharmacology, Kurume University School of Medicine
- Shigeyoshi Fujisawa
- Laboratory for Systems Neurophysiology, RIKEN Center for Brain Science
- Hideyuki Okano
- Department of Physiology, Keio University School of Medicine
- Masanari Itokawa
- Center for Medical Cooperation, Tokyo Metropolitan Institute of Medical Science
- Nobutaka Hirokawa
- Department of Cell Biology and Anatomy, Graduate School of Medicine, The University of Tokyo
- Yasuto Kunii
- Department of Neuropsychiatry, School of Medicine, Fukushima Medical University
- Akiyoshi Kakita
- Department of Pathology, Brain Research Institute, Niigata University
- Hirooki Yabe
- Department of Neuropsychiatry, School of Medicine, Fukushima Medical University
- Kazuya Iwamoto
- Department of Molecular Brain Science, Graduate School of Medical Sciences, Kumamoto University
- Kohji Meno
- Research& Development Department, MCBI Inc
- Takuya Katagiri
- Department of Pharmacy, Faculty of Pharmacy, Iryo Sosei University
- Brian Dean
- The Florey Institute of Neuroscience and Mental Health, Howard Florey Laboratories, The University of Melbourne
- Kazuhiko Uchida
- Department of Molecular Oncology, Division of Biomedical Science, Faculty of Medicine, University of Tsukuba
- Hideo Kimura
- Department of Pharmacology, Sanyo‐Onoda City University
- Takeo Yoshikawa
- Laboratory of Molecular Psychiatry, RIKEN Center for Brain Science
- DOI
- https://doi.org/10.15252/emmm.201910695
- Journal volume & issue
-
Vol. 11,
no. 12
pp. 1 – 24
Abstract
Abstract Mice with the C3H background show greater behavioral propensity for schizophrenia, including lower prepulse inhibition (PPI), than C57BL/6 (B6) mice. To characterize as‐yet‐unknown pathophysiologies of schizophrenia, we undertook proteomics analysis of the brain in these strains, and detected elevated levels of Mpst, a hydrogen sulfide (H2S)/polysulfide‐producing enzyme, and greater sulfide deposition in C3H than B6 mice. Mpst‐deficient mice exhibited improved PPI with reduced storage sulfide levels, while Mpst‐transgenic (Tg) mice showed deteriorated PPI, suggesting that “sulfide stress” may be linked to PPI impairment. Analysis of human samples demonstrated that the H2S/polysulfides production system is upregulated in schizophrenia. Mechanistically, the Mpst‐Tg brain revealed dampened energy metabolism, while maternal immune activation model mice showed upregulation of genes for H2S/polysulfides production along with typical antioxidative genes, partly via epigenetic modifications. These results suggest that inflammatory/oxidative insults in early brain development result in upregulated H2S/polysulfides production as an antioxidative response, which in turn cause deficits in bioenergetic processes. Collectively, this study presents a novel aspect of the neurodevelopmental theory for schizophrenia, unraveling a role of excess H2S/polysulfides production.
Keywords
