Placental Neurosteroid Disruption in Preterm Birth: Impact on GABAergic Signaling in the Somatosensory Cortex
Open AccessPreterm birth is a global problem that affects 10% of pregnancies and always results in the premature loss of the placenta. As the interface between maternal and fetal circulation, the placenta is a crucial organ for healthy pregnancy and fetal development. Thus, preterm birth may have devastating consequences due to the loss of placental support. This loss includes critical neurosteroids that the fetus cannot yet make, such as allopregnanolone (ALLO). Our findings reveal that cholesterol biosynthesis genes are dysregulated in human preterm placenta compared to term, consistent with gestational regulation of neurosteroids. Since the loss of placental steroids has long been hypothesized as a contributing factor in the etiology of neurological disorders associated with prematurity, we investigated the consequences of placental ALLO insufficiency on the development of the somatosensory cortex using the novel Akr1c14Cyp19plKO mouse model. Here we show that placental ALLO is essential for neural proliferation and cell cycling in the embryonic cortex. Mice without placental ALLO exhibit losses in principal cells and interneurons, as well as sex-specific reductions to spontaneous inhibitory post-synaptic currents. This is accompanied by deficits in somatosensory specific behavior in female mice without placental ALLO. Mechanistically, these alterations appear to be the consequence of reduced GABAA receptor (GABAA-R) potentiation by ALLO. During postnatal development, GABAA-R subunit δ and potassium-chloride transporter 2 (KCC2) are dynamically and temporally regulated in a sex-specific manner to potentially compensate for in-utero ALLO loss. Overall this work presents a novel link between placental neurosteroids, fetal brain development and long-term outcomes, while introducing new techniques to study the consequences of placental functioning in humans and in mice.
- All rights reserved
Notice to Authors
If you are the author of this work and you have any questions about the information on this page, please use the Contact form to get in touch with us.