Abstract
Compromised placental function or premature loss has been linked to diverse neurodevelopmental disorders. Here we show that placenta allopregnanolone (ALLO), a progesterone-derived GABA-A receptor (GABAAR) modulator, reduction alters neurodevelopment in a sex-linked manner. A new conditional mouse model, in which the gene encoding ALLO’s synthetic enzyme (akr1c14) is specifically deleted in trophoblasts, directly demonstrated that placental ALLO insufficiency led to cerebellar white matter abnormalities that correlated with autistic-like behavior only in male offspring. A single injection of ALLO or muscimol, a GABAAR agonist, during late gestation abolished these alterations. Comparison of male and female human preterm infant cerebellum also showed sex-linked myelination marker alteration, suggesting similarities between mouse placental ALLO insufficiency and human preterm brain development. This study reveals a new role for a placental hormone in shaping brain regions and behaviors in a sex-linked manner. Placental hormone replacement might offer novel therapeutic opportunities to prevent later neurobehavioral disorders.
Highlights
Neuroplacentology is a term coined to describe an emerging research area that aims to understand the influence of placental function on the developing brain
Our study empirically defines a critical role for a specific placental hormone that can alter fetal brain development in late gestation with postnatal developmental consequences
We focused on ALLO because this placental steroid hormone normally peaks in the second half of gestation, when placental insufficiency becomes evident and when preterm birth occurs
Summary
Neuroplacentology is a term coined to describe an emerging research area that aims to understand the influence of placental function on the developing brain. Many events, including infection, malnutrition and genetic abnormalities, can disrupt placental function or, as in preterm birth, can abruptly change the hormonal environment of the developing brain. In fetal sheep and guinea pigs, brain ALLO is increased in response to immune challenge, hypoxia and other acute prenatal stressors Blocking this increase pharmacologically with finasteride, a 5α-reductase inhibitor that blocks ALLO production, leads to increased apoptosis, excitotoxicity and impaired myelination, in males[5]. These observations support an endogenous neuroprotective role for ALLO and a potential therapeutic efficacy of ALLO analogs as central nervous system drugs but do not directly connect specific placental endocrine functions to changes in neurodevelopment. Understanding how specific placental hormones shape normal brain development and how placental loss or dysfunction contributes to the neurological impairments in those born extremely preterm or after compromised pregnancies lays the groundwork for developing hormone replacement strategies to maintain the normal developmental milieu and protect the brain from further injury
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