The perinatal mice administered prostaglandin E2 develop psychobehavioral and neuronal impairments in adults

[Speaker] Hirotake Hida:1,2
[Co-author] Akihiro Mouri:3, Kentaro Mori:1, Saori Takeuchi:1, Toshitaka Nabeshima:3, Kiyofumi Yamada:2, Norio Ozaki:4, Tomoyuki Furuyashiki:5, Shuh Narumiya:6, Yukihiro Noda:1
1:Division of Clinical Sciences and Neuropsychopharmacology, Meijo University Faculty and Graduate School of Pharmacy, Japan, 2:Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan, 3:Advanced Diagnostic System Research Laboratory, Fujita Health University Graduate School of Health Sciences, Toyoake, Aichi, Japan, 4:Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan, 5:Division of Pharmacology, Kobe University Graduate School of Medicine, Kobe, Japan, 6:Medical Innovation Center, Kyoto Univ Sch Med, Kyoto University Graduate School of Medicine, Kyoto, Japan

Background: Preclinical and clinical evidence suggest that exposure to perinatal inflammatory mediators such as pro-inflammatory cytokines and prostaglandins is known as risk factors for development of psychiatric disorders. Our previous study revealed that various inflammatory mediators were induced by perinatal exposure to environmental factors; viral infection [injection of polyinosinic-polycytidylic acid (PolyI:C)], hypoxia (exposure to CO2), and neglect (separation from the dams), and further the prostaglandin E2 (PGE2) may be one of common inflammatory mediators induced by environmental factors. However, the roles of PGE2 in the development of psychiatric disorders are not yet clear. The present study was designed to examine effects of a perinatal PGE2 administration on the psychobehaviors in adults and effects of PGE2 on neurite outgrowth in the primary culture.
Methods: The PGE2 administered at the dose of 10mg/kg/day to C57BL/6N mice during PD 2-6. Emotional and cognitive behavioral analysis were performed in PD35 and PD70. We investigated the effect of PGE2-EP1 receptor antagonist, indomethacin (cyclooxygenase inhibitor), and EP1 KO mice on behavioral impairment in mice administered of PGE2. Hippocampal cultures were prepared from gestational day 13-15 old mice, and affects of exposure to PGE2 on neurite growth were examined.
Results: The mice administered PGE2 during PD2-6 exhibited impairment of social behaviors, object recognition memory, and pre-pulse inhibition (PPI) in PD70 (adults), but not PD35 (adolescents). These behavioral impairments were attenuated by blockade of PGE2-EP1 receptor, indomethacin, and genetic deletion of PGE2-EP1 receptor. In the primary culture, the PGE2 induced the decrease in neurite growth. Such neuronal change was also prevented by PGE2-EP1 receptor antagonist.
Conclusion: Our findings suggest that PGE2 is one of potential common inflammatory mediators induced by environmental factors, and PGE2 plays a crucial role in the development of behavioral and neuronal impairments, which are associated with activation of PGE2-EP1 receptor.

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