TY - JOUR
T1 - Placental endocrine function shapes cerebellar development and social behavior
AU - Vacher, Claire Marie
AU - Lacaille, Helene
AU - O’Reilly, Jiaqi J.
AU - Salzbank, Jacquelyn
AU - Bakalar, Dana
AU - Sebaoui, Sonia
AU - Liere, Philippe
AU - Clarkson-Paredes, Cheryl
AU - Sasaki, Toru
AU - Sathyanesan, Aaron
AU - Kratimenos, Panagiotis
AU - Ellegood, Jacob
AU - Lerch, Jason P.
AU - Imamura, Yuka
AU - Popratiloff, Anastas
AU - Hashimoto-Torii, Kazue
AU - Gallo, Vittorio
AU - Schumacher, Michael
AU - Penn, Anna A.
N1 - Funding Information:
We thank G. Leone for providing us with Cyp19a-Cre mice. We also would like to express our gratitude to J. Scafidi, L.-J. Chew and I. Papazoglou for their comments on the manuscript. We thank M. Yang, the head of the Neurobehavioral Core at Columbia University Medical Center, for giving us access to the equipment. We thank E. Rafikian for scoring the ultrasonic vocalizations. We also thank the contribution of families to the NIH NeuroBioBank, as well as J. Cottrell (NIH NeuroBioBank), who assisted us throughout the process of human tissue selection. We gratefully acknowledge the Children’s Research Animal Facility, directed by J. Bradford, for taking care of our mouse colonies and the DC-IDDRC Animal Neurobehavioral Core, headed by J. Corbin, for providing advice, space and equipment to conduct the behavioral phenotyping of our mice. Light and confocal microscopic analyses were carried out at the DC-IDDRC’s Cell and Tissue Microscopy Core. The DC-IDDRC cores are supported by National Institutes of Health NICHD U54HD090257 (V.G.). This work was funded by National Institutes of Health grants R01HD092593 and 3R01HD092593-S1 (A.A.P.), R37NS109478 (V.G.) and F31HD098886 (J.J.O.), the Simons Foundation (SFARI Pilot Award no. 572832; A.A.P.), the Children’s National Board of Visitors (A.A.P. and V.G.) and the Research Foundation of Cerebral Palsy Alliance (no. 3720; A.A.P.).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/10
Y1 - 2021/10
N2 - 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.
AB - 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.
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U2 - 10.1038/s41593-021-00896-4
DO - 10.1038/s41593-021-00896-4
M3 - Article
C2 - 34400844
AN - SCOPUS:85112680827
SN - 1097-6256
VL - 24
SP - 1392
EP - 1401
JO - Nature Neuroscience
JF - Nature Neuroscience
IS - 10
ER -