Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 116, Issue 14, Pages 7083-7088Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1819234116
Keywords
epoxy fatty acid; ER stress; iPSCs; maternal infection; prevention
Categories
Funding
- Japan Society for the Promotion of Science (JSPS) KAKENHI [18K15439, 17H04243]
- Japan Agency for Medical Research and Development [JP18dm0107119, JP18dm0107083]
- Ministry of Education, Culture, Sports, Science and Technology, Japan [JP18H05435]
- National Institute of Environmental Health Sciences (NIEHS) [R01 ES002710]
- NIEHS Superfund Program Grant [P42 ES004699]
- Nurture of Creative Research Leaders in Immune System Regulation and Innovative Therapeutics Program of Chiba University
- JSPS
- Grants-in-Aid for Scientific Research [18K15439] Funding Source: KAKEN
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Maternal infection during pregnancy increases risk of neurodevelopmental disorders such as schizophrenia and autism spectrum disorder (ASD) in offspring. In rodents, maternal immune activation (MIA) yields offspring with schizophrenia- and ASD-like behavioral abnormalities. Soluble epoxide hydrolase (sEH) plays a key role in inflammation associated with neurodevelopmental disorders. Here we found higher levels of sEH in the prefrontal cortex (PFC) of juvenile offspring after MIA. Oxylipin analysis showed decreased levels of epoxy fatty acids in the PFC of juvenile offspring after MIA, supporting increased activity of sEH in the PFC of juvenile offspring. Furthermore, expression of sEH (or EPHX2) mRNA in induced pluripotent stem cell-derived neurospheres from schizophrenia patients with the 22q11.2 deletion was higher than that of healthy controls. Moreover, the expression of EPHX2 mRNA in postmortem brain samples (Brodmann area 9 and 40) from ASD patients was higher than that of controls. Treatment with 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl)urea (TPPU), a potent sEH inhibitor, in juvenile offspring from prenatal day (P) 28 to P56 could prevent cognitive deficits and loss of parvalbumin (PV) immunoreactivity in the medial PFC of adult offspring after MIA. In addition, dosing of TPPU to pregnant mothers from E5 to P21 could prevent cognitive deficits, and social interaction deficits and PV immunoreactivity in the medial prefrontal cortex of juvenile offspring after MIA. These findings suggest that increased activity of sEH in the PFC plays a key role in the etiology of neurodevelopmental disorders in offspring after MIA. Therefore, sEH represents a promising prophylactic or therapeutic target for neurodevelopmental disorders in offspring after MIA.
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