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Microglia alter sex-specific cerebellar myelination following placental hormone loss

Author

Listed:
  • 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)

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.

Suggested Citation

  • Jacquelyn Salzbank & Helene Lacaille & Jenah Gaby & Jiaqi J. O’Reilly & Michael Kissner & Claire-Marie Vacher & Anna A. Penn, 2025. "Microglia alter sex-specific cerebellar myelination following placental hormone loss," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-64814-z
    DOI: 10.1038/s41467-025-64814-z
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    References listed on IDEAS

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    1. Alastair M. Hosie & Megan E. Wilkins & Helena M. A. da Silva & Trevor G. Smart, 2006. "Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites," Nature, Nature, vol. 444(7118), pages 486-489, November.
    2. Katherine A. Fitzgerald & Eva M. Palsson-McDermott & Andrew G. Bowie & Caroline A. Jefferies & Ashley S. Mansell & Gareth Brady & Elizabeth Brint & Aisling Dunne & Pearl Gray & Mary T. Harte & Diane M, 2001. "Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction," Nature, Nature, vol. 413(6851), pages 78-83, September.
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