Microglia alter sex-specific cerebellar myelination following placental hormone loss

Jacquelyn Salzbank, Helene Lacaille, Jenah Gaby, Jiaqi J. O’Reilly, Michael Kissner, Claire-Marie Vacher and Anna A. Penn ()
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Jacquelyn Salzbank: New York-Presbyterian Morgan Stanley Children’s Hospital
Helene Lacaille: New York-Presbyterian Morgan Stanley Children’s Hospital
Jenah Gaby: New York-Presbyterian Morgan Stanley Children’s Hospital
Jiaqi J. O’Reilly: National Institutes of Health
Michael Kissner: Columbia University Medical Center
Claire-Marie Vacher: New York-Presbyterian Morgan Stanley Children’s Hospital
Anna A. Penn: New York-Presbyterian Morgan Stanley Children’s Hospital

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Placental dysfunction is linked to neurodevelopmental disorders, with males showing greater vulnerability to perinatal inflammation-mediated brain injuries. Using our transgenic mouse model, Akr1c14cyp19aKO (plKO), we investigate how reduced placental allopregnanolone (ALLO), an anti-inflammatory neurosteroid, contributes to sex-specific brain injury. plKO mice display sex-divergent cerebellar myelination and male-specific autism-like behaviors. Here we show that placental ALLO insufficiency triggers sex-divergent neuroinflammatory responses and microglial dysfunction. Sex-divergent differential expression of inflammatory genes and distinct inflammatory cytokine/chemokine patterns are seen in the placenta and the brain. Prostaglandin E2 (PGE2)-EP4 signaling is identified as a key regulator and, consistent with male plKO cerebellar hypermyelination, male microglial myelin phagocytosis is impaired by SIRPα-CD47 signaling changes. Postnatal manipulation of these critical pathways can normalize cerebellar myelin content and rescue abnormal behavior in male plKO mice. Sex-divergent microglial dysfunction and prostaglandin signaling drive male-biased neurodevelopmental impairments in our model, suggesting new therapeutic targets to improve brain development following placental dysfunction.

Date: 2025
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DOI: 10.1038/s41467-025-64814-z

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