Open AccessExcess hydrogen sulfide and polysulfides production underlies a schizophrenia pathophysiology
Author(s) -
Ide Masayuki,
Ohnishi Tetsuo,
Toyoshima Manabu,
Balan Shabeesh,
Maekawa Motoko,
ShimamotoMitsuyama Chie,
Iwayama Yoshimi,
Ohba Hisako,
Watanabe Akiko,
Ishii Takashi,
Shibuya Norihiro,
Kimura Yuka,
Hisano Yasuko,
Murata Yui,
Hara Tomonori,
Morikawa Momo,
Hashimoto Kenji,
Nozaki Yayoi,
Toyota Tomoko,
Wada Yuina,
Tanaka Yosuke,
Kato Tadafumi,
Nishi Akinori,
Fujisawa Shigeyoshi,
Okano Hideyuki,
Itokawa Masanari,
Hirokawa Nobutaka,
Kunii Yasuto,
Kakita Akiyoshi,
Yabe Hirooki,
Iwamoto Kazuya,
Meno Kohji,
Katagiri Takuya,
Dean Brian,
Uchida Kazuhiko,
Kimura Hideo,
Yoshikawa Takeo
Publication year - 2019
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201910695
Subject(s) - hydrogen sulfide , pathophysiology , schizophrenia (object oriented programming) , chemistry , medicine , sulfur , psychiatry , organic chemistry
Mice with the C3H background show greater behavioral propensity for schizophrenia, including lower prepulse inhibition ( PPI ), than C57 BL /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 (H 2 S)/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 H 2 S/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 H 2 S/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 H 2 S/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 H 2 S/polysulfides production.