Problems with the placenta, such as those that occur with preeclampsia and some infections, may cause defects in how the fetal brain develops. A new mouse model suggests that placental complications result in lower levels of a particular hormone, negatively impacting brain development and social behaviors, particularly in males (Vacher et al., Nat. Neurosci., 2021). The work was supported in part by a Pilot Award to SFARI Investigator Anna Penn.
The hormone allopregnanolone, or ALLO for short, is a progesterone-derived inhibitory (GABAergic) steroid that affects how brain cells communicate. ALLO is produced in the endocrine system, where it can cross into the brain itself. During pregnancy, the placenta supplies additional progesterone, causing increases in the concentration of ALLO in the fetal brain. In animal models, blocking ALLO production with drugs causes neuron damage and defects in myelin, the protective neuron sheath (Brunton et al., Prog. Neurobiol., 2014). This new study asked whether placental-driven increases in ALLO were specifically necessary for fetal brain health, locking the production of ALLO in the mouse placenta and confirming a critical role for placental ALLO in supporting healthy fetal brain development.
In this mouse model, the loss of maternally supplied placental ALLO caused fetal brains to have much less ALLO. This resulted in changes in myelin precursors and myelination in the cerebellum — a brain region important for sensorimotor behaviors and emotional control — with males showing more myelin and females somewhat less. Male offspring were also less likely to interact with other mice and showed increases in motor-based repetitive behaviors. Both the cerebellar myelin and behavioral effects reversed when the pregnant dams were given ALLO.
While these findings were in mice, the study also found that preterm infants — who have less time in the placenta — show similar sex-specific changes in cerebellar myelin. Preterm birth is also a risk factor for autism, a condition often characterized by changes in social behaviors and repetitive behaviors.
Interestingly, clinical trials are already underway for the use of synthetic forms of ALLO in treating some neuropsychiatric disorders — including major depression and fragile X syndrome. Synthetic ALLO, marketed as Zulresso, has also already been approved for the treatment of postpartum depression. The current data suggest that synthetic ALLO may be of use for placental dysfunctions as well, helping to promote healthy fetal brain development — though some caution is warranted, as detrimental effects seen in a portion of control mouse offspring suggest the right ALLO dosage may be critical.
Placental endocrine function shapes cerebellar development and social behavior.
Vacher C.-M., Lacaille H., O’Reilly J.J., Salzbank J., Bakalar D., Sebaoui S., Liere P., Clarkson-Paredes C., Sasaki T., Sathyanesan A., Kratimenos P., Ellegood J., Lerch J., Imamura Y., Popratiloff A., Hashimoto-Torii K., Gallo V., Schumacher M., Penn A. A.