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

Marius Schwabenland, Omar Mossad, Annika Sievert, Adam G. Peres, Elena Ringel, Sebastian Baasch, Julia Kolter, Giulia Cascone, Nikolaos Dokalis, Andreas Vlachos, Zsolt Ruzsics, Philipp Henneke, Marco Prinz and Thomas Blank ()
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Marius Schwabenland: University of Freiburg
Omar Mossad: University of Freiburg
Annika Sievert: University of Freiburg
Adam G. Peres: University of Freiburg
Elena Ringel: University of Freiburg
Sebastian Baasch: University of Freiburg, Faculty of Medicine, University of Freiburg
Julia Kolter: University of Freiburg, Faculty of Medicine, University of Freiburg
Giulia Cascone: University of Freiburg
Nikolaos Dokalis: University of Freiburg
Andreas Vlachos: University of Freiburg
Zsolt Ruzsics: University of Freiburg
Philipp Henneke: University of Freiburg, Faculty of Medicine, University of Freiburg
Marco Prinz: University of Freiburg
Thomas Blank: University of Freiburg

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-38373-0

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