TY - JOUR
T1 - Modulating microglia activation prevents maternal immune activation induced schizophrenia-relevant behavior phenotypes via arginase 1 in the dentate gyrus
AU - Xia, Yucen
AU - Zhang, Zhiqing
AU - Lin, Weipeng
AU - Yan, Jinglan
AU - Zhu, Chuan’an
AU - Yin, Dongmin
AU - He, Su
AU - Su, Yang
AU - Xu, Nenggui
AU - Caldwell, Robert William
AU - Yao, Lin
AU - Chen, Yongjun
N1 - Funding Information:
This work was supported by National Key R&D Program of China (Grant 2019YFC1712105 to Y Chen); National Natural Science Fund of China (Grants 31600843 to Y Xia and 81973948 to Y Chen); Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2016, Grant to Y Chen); Science and Technology Program of Guangdong (Grant 2018B030334001 to Y Chen); Research Grant of Guangdong Province Key Laboratory of Psychiatric Disorders (N201801 to Y Chen) and Innovation Team Program of Guangdong Provincial Department of education (2018KCXTD006 to Y Chen and 2017KCXTD006 to N Xu); Science and Technology Program of Guangzhou, China (Grant No: 202002030190 to L Yao). The authors declare no conflict of interest.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to American College of Neuropsychopharmacology.
PY - 2020/10/1
Y1 - 2020/10/1
N2 - Prenatal infection during pregnancy increases the risk for developing neuropsychiatric disorders such as schizophrenia. This is linked to an inflammatory microglial phenotype in the offspring induced by maternal immune activation (MIA). Microglia are crucial for brain development and maintenance of neuronal niches, however, whether and how their activation is involved in the regulation of neurodevelopment remains unclear. Here, we used a MIA rodent model in which polyinosinic: polycytidylic acid (poly (I:C)) was injected into pregnant mice. We found fewer parvalbumin positive (PV+) cells and impaired GABAergic transmission in the dentate gyrus (DG), accompanied by schizophrenia-like behavior in the adult offspring. Minocycline, a potent inhibitor of microglia activation, successfully prevented the above-mentioned deficits in the offspring. Furthermore, by using microglia-specific arginase 1 (Arg1) ablation as well as overexpression in DG, we identified a critical role of Arg1 in microglia activation to protect against poly (I:C) imparted neuropathology and altered behavior in offspring. Taken together, our results highlight that Arg1-mediated alternative activation of microglia are potential therapeutic targets for psychiatric disorders induced by MIA.
AB - Prenatal infection during pregnancy increases the risk for developing neuropsychiatric disorders such as schizophrenia. This is linked to an inflammatory microglial phenotype in the offspring induced by maternal immune activation (MIA). Microglia are crucial for brain development and maintenance of neuronal niches, however, whether and how their activation is involved in the regulation of neurodevelopment remains unclear. Here, we used a MIA rodent model in which polyinosinic: polycytidylic acid (poly (I:C)) was injected into pregnant mice. We found fewer parvalbumin positive (PV+) cells and impaired GABAergic transmission in the dentate gyrus (DG), accompanied by schizophrenia-like behavior in the adult offspring. Minocycline, a potent inhibitor of microglia activation, successfully prevented the above-mentioned deficits in the offspring. Furthermore, by using microglia-specific arginase 1 (Arg1) ablation as well as overexpression in DG, we identified a critical role of Arg1 in microglia activation to protect against poly (I:C) imparted neuropathology and altered behavior in offspring. Taken together, our results highlight that Arg1-mediated alternative activation of microglia are potential therapeutic targets for psychiatric disorders induced by MIA.
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U2 - 10.1038/s41386-020-0743-7
DO - 10.1038/s41386-020-0743-7
M3 - Article
C2 - 32599605
AN - SCOPUS:85087006832
SN - 0893-133X
VL - 45
SP - 1896
EP - 1908
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
IS - 11
ER -