Year: 2025
Type: article
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. Here authors reveal that placental hormone insufficiency can cause sex-linked brain inflammatory responses in mice. Altered microglial and prostaglandin signalling drive male-biased impairments, highlighting therapeutic targets for neurodevelopmental disorders.
Source: Nature Communications
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: U.S. Department of Health and Human Services, Simons Foundation, Simons Foundation Autism Research Initiative, National Institutes of Health, Irving Medical Center, Columbia University, NIH Office of the Director, National Institute of Neurological Disorders and Stroke, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: G4252471225, G4568741376, G5197149029, Millipore Sigma ImageStream-X Mark II Imaging Cytometer, G5875207346, G6090938583, Therapeutic agents to prevent developmental neuroimpairment after placental hormone loss, G7541001557, G8159799999, Advanced Graduate Training Program in Neurobiology & Behavior, G9000160414, G9000181678, Novel Roles of Placental Allopregnanolone in Brain Development and Injury
OpenAlex ID: W4415989496