Placental endocrine function shapes cerebellar development and social behavior

Claire Marie Vacher, Helene Lacaille, Jiaqi J. O’Reilly, Jacquelyn Salzbank, Dana Bakalar, Sonia Sebaoui, Philippe Liere, Cheryl Clarkson-Paredes, Toru Sasaki, Aaron Sathyanesan, Panagiotis Kratimenos, Jacob Ellegood, Jason P. Lerch, Yuka Imamura, Anastas Popratiloff, Kazue Hashimoto-Torii, Vittorio Gallo, Michael Schumacher, Anna A. Penn

Research output: Contribution to journalArticlepeer-review

48 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1392-1401
Number of pages10
JournalNature Neuroscience
Issue number10
StatePublished - Oct 2021

All Science Journal Classification (ASJC) codes

  • General Neuroscience


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