Journal
EMBO MOLECULAR MEDICINE
Volume 11, Issue 12, Pages -Publisher
WILEY
DOI: 10.15252/emmm.201910695
Keywords
energy metabolism; epigenetics; hydrogen sulfide and polysulfides; prepulse inhibition; proteomics
Categories
Funding
- Japan Agency for Medical Research and Development (AMED) [JP18dm0107083, JP19dm0107083, JP18dm0107085, JP19dm0107119, JP19dm0908001, 19dm0107086, 19dm0107107]
- MEXT [JP18H05435, JP18H05428, JP16H06277]
- JSPS KAKENHI [JP17H01574]
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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.
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