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Modulating microglia activation prevents maternal immune activation induced schizophrenia-relevant behavior phenotypes via arginase 1 in the dentate gyrus.

ABSTRACT: 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.

SUBMITTER: Xia Y

PROVIDER: S-EPMC7608378 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Dentate gyrus volume deficit in schizophrenia.

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p16Ink4a Prevents the Activation of Aged Quiescent Dentate Gyrus Stem Cells by Physical Exercise.

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Detection of an immature dentate gyrus feature in human schizophrenia/bipolar patients.

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Modeling intrahippocampal effects of anterior hippocampal hyperactivity relevant to schizophrenia using chemogenetic excitation of long axis-projecting mossy cells in the mouse dentate gyrus.

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Activation of local inhibitory circuits in the dentate gyrus by adult-born neurons.

Project description:Robust incorporation of new principal cells into pre-existing circuitry in the adult mammalian brain is unique to the hippocampal dentate gyrus (DG). We asked if adult-born granule cells (GCs) might act to regulate processing within the DG by modulating the substantially more abundant mature GCs. Optogenetic stimulation of a cohort of young adult-born GCs (0 to 7 weeks post-mitosis) revealed that these cells activate local GABAergic interneurons to evoke strong inhibitory input to mature GCs. Natural manipulation of neurogenesis by aging-to decrease it-and housing in an enriched environment-to increase it-strongly affected the levels of inhibition. We also demonstrated that elevating activity in adult-born GCs in awake behaving animals reduced the overall number of mature GCs activated by exploration. These data suggest that inhibitory modulation of mature GCs may be an important function of adult-born hippocampal neurons. © 2015 Wiley Periodicals, Inc.

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