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  • Basic Science Article
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Maternal immune activation alters fetal and neonatal microglia phenotype and disrupts neurogenesis in mice

Abstract

Background

Activation of microglia, increase in cortical neuron density, and reduction in GABAergic interneurons are some of the key findings in postmortem autism spectrum disorders (ASD) subjects. The aim of this study was to investigate how maternal immune activation (MIA) programs microglial phenotypes and abnormal neurogenesis in offspring mice.

Methods

MIA was induced by injection of lipopolysaccharide (LPS, i.p.) to pregnant mice at embryonic (E) day 12.5. Microglial phenotypes and neurogenesis were investigated between E15.5 to postnatal (P) day 21 by immunohistochemistry, flow cytometry, and cytokine array.

Results

MIA led to a robust increase in fetal and neonatal microglia in neurogenic regions. Homeostatic E15.5 and P4 microglia are heterogeneous, consisting of M1 (CD86+/CD206−) and mixed M1/M2 (CD86+/CD206+)-like subpopulations. MIA significantly reduced M1 but increased mixed M1/M2 microglia, which was associated with upregulation of numerous cytokines with pleotropic property. MIA resulted in a robust increase in Ki67+/Nestin+ and Tbr2+ neural progenitor cells in the subventricular zone (SVZ) of newborn mice. At juvenile stage, a male-specific reduction of Parvalbumin+ but increase in Reelin+ interneurons in the medial prefrontal cortex was found in MIA offspring mice.

Conclusions

MIA programs microglia towards a pleotropic phenotype that may drive excessive neurogenesis in ASD patients.

Impact

  • Maternal immune activation (MIA) alters microglial phenotypes in the brain of fetal and neonatal mouse offspring.

  • MIA leads to excessive proliferation and overproduction of neural progenitors in the subventricular zone (SVZ).

  • MIA reduces parvalbumin+ while increases Reelin+ interneurons in the prefrontal cortex.

  • Our study sheds light on neurobiological mechanisms of abnormal neurogenesis in certain neurodevelopmental disorders, such as autism spectrum disorder (ASD).

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Fig. 1: MIA leads a robust activation of microglia in the brains of E15.5 and P1 offspring.
Fig. 2: Flow cytometry analysis of microglia phenotypes.
Fig. 3: MIA stimulates proliferation of NSCs in the offspring mouse brain.
Fig. 4: Overproduction of Tbr2+ NPCs in the MIA offspring at P1.
Fig. 5: MIA causes abnormal differentiation of PV+ and Reelin+ interneurons.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request

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Acknowledgements

Flow cytometry experiments were performed at the UMMC Cancer Center and Research Institute Flow Cytometry Core Facility, which is supported in part through the UMMC Mississippi Center of Excellence in Perinatal Research (MS-CEPR)-COBRE (P20GM121334). We would like to thank Dr. Ava Bengten, Dr. Melanie Wilson, and Dr. Jon Person for their advice and technical assistance in FACS experiments. Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health under Award Number P20GM121334. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Y.P. and A.B. conceived the study. M.L., A.B., and Y.P. contributed to the study design and drafted the manuscript. M.L., S.L., K.C., S.R., and Y.P. performed experiments. M.L., N.O., L.-W.F., and Y.P. contributed to data analysis.

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Correspondence to Abhay Bhatt or Yi Pang.

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Loayza, M., Lin, S., Carter, K. et al. Maternal immune activation alters fetal and neonatal microglia phenotype and disrupts neurogenesis in mice. Pediatr Res 93, 1216–1225 (2023). https://doi.org/10.1038/s41390-022-02239-w

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