Prenatal immune stress blunts microglia reactivity, impairing neurocircuitry

Lindsay N. Hayes, Kyongman An, Elisa Carloni, Fangze Li, Elizabeth Vincent, Chloë Trippaers, Manish Paranjpe, Gül Dölen, Loyal A. Goff, Adriana Ramos, Shin-ichi Kano and Akira Sawa ()
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Lindsay N. Hayes: Johns Hopkins University School of Medicine
Kyongman An: Johns Hopkins University School of Medicine
Elisa Carloni: Johns Hopkins University School of Medicine
Fangze Li: Johns Hopkins University School of Medicine
Elizabeth Vincent: Johns Hopkins University School of Medicine
Chloë Trippaers: Johns Hopkins University School of Medicine
Manish Paranjpe: Johns Hopkins University School of Medicine
Gül Dölen: Johns Hopkins University School of Medicine
Loyal A. Goff: Johns Hopkins University School of Medicine
Adriana Ramos: Johns Hopkins University School of Medicine
Shin-ichi Kano: Johns Hopkins University School of Medicine
Akira Sawa: Johns Hopkins University School of Medicine

Nature, 2022, vol. 610, issue 7931, 327-334

Abstract: Abstract Recent studies suggested that microglia, the primary brain immune cells, can affect circuit connectivity and neuronal function1,2. Microglia infiltrate the neuroepithelium early in embryonic development and are maintained in the brain throughout adulthood3,4. Several maternal environmental factors—such as an aberrant microbiome, immune activation and poor nutrition—can influence prenatal brain development5,6. Nevertheless, it is unknown how changes in the prenatal environment instruct the developmental trajectory of infiltrating microglia, which in turn affect brain development and function. Here we show that, after maternal immune activation (MIA) in mice, microglia from the offspring have a long-lived decrease in immune reactivity (blunting) across the developmental trajectory. The blunted immune response was accompanied by changes in chromatin accessibility and reduced transcription factor occupancy of the open chromatin. Single-cell RNA-sequencing analysis revealed that MIA does not induce a distinct subpopulation but, rather, decreases the contribution to inflammatory microglia states. Prenatal replacement of microglia from MIA offspring with physiological infiltration of naive microglia ameliorated the immune blunting and restored a decrease in presynaptic vesicle release probability onto dopamine receptor type-two medium spiny neurons, indicating that aberrantly formed microglia due to an adverse prenatal environment affect the long-term microglia reactivity and proper striatal circuit development.

Date: 2022
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DOI: 10.1038/s41586-022-05274-z

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