Neonatal immune challenge poses a sex-specific risk for epigenetic microglial reprogramming and behavioral impairment

While the precise processes underlying a sex bias in the development of central nervous system (CNS) disorders are unknown, there is growing evidence that an early life immune activation can contribute to the disease pathogenesis. When we mimicked an early systemic viral infection or applied murine...

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Bibliographic Details
Published in:	Nature communications Vol. 14; no. 1; p. 2721
Main Authors:	Schwabenland, Marius, Mossad, Omar, Sievert, Annika, Peres, Adam G., Ringel, Elena, Baasch, Sebastian, Kolter, Julia, Cascone, Giulia, Dokalis, Nikolaos, Vlachos, Andreas, Ruzsics, Zsolt, Henneke, Philipp, Prinz, Marco, Blank, Thomas
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 11-05-2023 Nature Publishing Group Nature Portfolio
Subjects:	13 13/1 13/51 14 14/19 14/63 38 38/91 631/250/371 631/378/2571 64 64/60 Adolescents Animals Brain CD3 antigen Central nervous system Central Nervous System Diseases - pathology Cognition Cytomegalovirus Epigenesis, Genetic Epigenetics Female Females Hippocampus Humanities and Social Sciences Immune system Immunological synapses Interferon-gamma - genetics Lymphocytes Lymphocytes T Male Males Mice Microglia Microglia - pathology multidisciplinary Neonates Parenchyma Pathogenesis Phagocytes Science Science (multidisciplinary) Sex Sex differences Social behavior Social interactions Synapses γ-Interferon
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Summary:	While the precise processes underlying a sex bias in the development of central nervous system (CNS) disorders are unknown, there is growing evidence that an early life immune activation can contribute to the disease pathogenesis. When we mimicked an early systemic viral infection or applied murine cytomegalovirus (MCMV) systemically in neonatal female and male mice, only male adolescent mice presented behavioral deficits, including reduced social behavior and cognition. This was paralleled by an increased amount of infiltrating T cells in the brain parenchyma, enhanced interferon-γ (IFNγ) signaling, and epigenetic reprogramming of microglial cells. These microglial cells showed increased phagocytic activity, which resulted in abnormal loss of excitatory synapses within the hippocampal brain region. None of these alterations were seen in female adolescent mice. Our findings underscore the early postnatal period’s susceptibility to cause sex-dependent long-term CNS deficiencies following infections. Early life inflammation has been linked to neurodevelopmental outcomes. Here the authors show that in mice, neonatal immune challenge results in CD3 + T cell infiltration to brain parenchyma, and microglial activation, to a greater extent in males than females.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-023-38373-0