Summary: Research in experimental models suggests that a sudden drop or loss of the placental hormone allopregnanolone (ALLO) during pregnancy increases the likelihood that offspring will develop autism-like brain changes and behaviors. In these preclinical models, a single prenatal injection of ALLO prevented the brain abnormalities and social deficits linked to autism spectrum disorder (ASD).
Source: Children’s National Hospital
Overview: A study using experimental models indicates that allopregnanolone, a neurosteroid produced by the placenta, is critical for normal fetal brain development. When placental production of ALLO decreases abruptly—as can happen with premature birth—offspring are more likely to show structural brain changes and behavioral traits that resemble autism spectrum disorder. The research team from Children’s National Hospital presented these findings at the Neuroscience 2019 annual meeting.
“To our knowledge, no other research group has directly examined how placental allopregnanolone contributes to brain development and long-term behavior,” says Claire-Marie Vacher, Ph.D., lead author of the study. “Our results show that targeted loss of ALLO in the womb causes lasting structural changes in the cerebellum, a region essential for motor coordination, balance and aspects of social cognition, and that loss increases the risk of autism-like outcomes in offspring.”
Public health context: according to the Centers for Disease Control and Prevention, roughly 1 in 10 infants is born preterm (before 37 weeks’ gestation), and about 1 in 59 children is diagnosed with autism spectrum disorder. Because placental hormones rise and fall with pregnancy progression, interruptions to placental function in preterm birth could have downstream effects on the developing brain.
ALLO production by the placenta increases during the second trimester and reaches its highest levels as pregnancy approaches full term. To model what happens when ALLO is disrupted, the research team developed a transgenic preclinical model in which a gene essential for ALLO synthesis in the placenta was deleted. When placental ALLO production fell in these models, offspring experienced persistent neurodevelopmental alterations that depended on sex and brain region.
Structural findings: The most prominent abnormalities were found in the cerebellar white matter. Specifically, researchers observed increased thickness of myelin, the lipid-rich insulating layer that surrounds nerve fibers and supports signal transmission. These structural changes in white matter indicate that prenatal ALLO disruption can alter the organization and protective coverings of neural circuits in the cerebellum.
Behavioral findings: Male offspring with an abrupt prenatal reduction in ALLO showed increased repetitive behaviors and reduced social interactions—two behavioral domains commonly affected in individuals with autism spectrum disorder. The sex-specific pattern observed in these experimental models highlights the need to consider biological sex in studies of prenatal influences on neurodevelopment.
Treatment implications in models: Importantly, a single injection of ALLO given during pregnancy was sufficient in the experimental models to prevent both the cerebellar structural changes and the atypical social behaviors. While these results are preclinical and do not imply immediate applicability to humans, they suggest that restoring or stabilizing key placental neurosteroids during critical windows of fetal brain development could be a promising area for further research.
New research direction: The team has launched a focused research program they call “neuroplacentology,” aimed at better understanding how the placenta and its hormones shape fetal and newborn brain development. By studying placental function and its interactions with the developing brain, investigators hope to identify mechanisms that underlie risk for neurodevelopmental disorders and potential points of intervention.
“Our data provide new evidence that placental hormones play an important role in programming the developing brain,” Vacher notes. “Understanding how placental signals contribute to neural circuit formation and behavior could open new avenues for preventing or reducing risk for neurodevelopmental disorders associated with premature birth and placental dysfunction.”
Source:
Children’s National Hospital
Media Contact:
Diedtra Henderson – Children’s National Hospital
Image Source:
The image is credited to Children’s National Hospital.
Original Research: The study was presented at the Neuroscience 2019 meeting in Chicago.