Newly reported research in mice is the first to provide direct evidence that loss of a placental hormone can alter long-term brain development in offspring. The study, headed by researchers in the laboratory of Anna Penn, MD, PhD, now at Columbia University Vagelos College of Physicians and Surgeons, and previously at Children’s National Hospital in Washington, D.C. found that that reducing amounts of a single hormone called allopregnanolone(ALLO) in the placenta caused brain and behavior alterations in male offspring that resemble changes seen in some people with autism spectrum disorder (ASD). The developing fetal brain would normally encounter the hormone in the second half of pregnancy, and the researchers also demonstrated that both brain structural and behavioral changes in male offspring could be prevented with a single injection of ALLO given during late pregnancy. They suggest their findings point to the potential future use of placental hormone replacement as an approach to preventing certain neurobehavioral disorders.

“Our study provides new and intriguing insights into how the loss of placental hormones—which happens in preterm birth or if the placenta stops working well during pregnancy—can lead to long-term structural changes in the brain that increase the risk for autism or other neuropsychiatric disorders,” said Claire-Marie Vacher, PhD, assistant professor of neonatal sciences in the Department of Pediatrics at Columbia University’s Vagelos College of Physicians and Surgeons. “What’s encouraging is that these disorders may be preventable if diagnosed and treated early.” Vacher is lead author of the team’s published paper in Nature Neuroscience, which is titled “Placental endocrine function shapes cerebellar development and social behaviour,” in which the authors conclude, “Placental hormone replacement might offer novel therapeutic opportunities to prevent later neurobehavioral disorders.”

Preterm birth has been shown to increase the risk of autism spectrum disorders and other developmental problems, particularly in males. The more premature a baby is, the greater the risk of either motor or cognitive deficits.

Similarly, the authors wrote, “Placental dysfunction or pathology has been associated with abnormal neurodevelopment, but the causal mechanisms remain largely unknown.” The placenta is an organ that provides the fetus with oxygen and nutrients and removes waste products. It also produces hormones, including high levels of ALLO in late pregnancy that may influence brain development. Penn, now the L. Stanley James Associate Professor of Pediatrics at Columbia University Vagelos College of Physicians and Surgeons and chief of neonatology at Columbia and NewYork-Presbyterian Morgan Stanley Children’s Hospital, coined the term “neuroplacentology” to describe this new field of research connecting placental function to brain development.

About one in 10 infants is born prematurely—and is thus deprived of normal levels of ALLO and other hormones—and many more pregnancies have poor placental function. However, as the authors noted, much of the research connecting compromised placental function to brain injury has focused on gas exchange or nutritional programming, and neglected the placenta’s key neuroendocrine role. “Many events, including infection, malnutrition and genetic abnormalities, can disrupt placental function or, as in preterm birth, can abruptly change the hormonal environment of the developing brain,” the authors wrote. “Such changes might alter early brain development or increase the susceptibility of the immature brain to damage.”

The team reasoned that ALLO, a progesterone-derived GABA-A receptor (GABAAR) modulator, might represent a “key placental hormone in shaping fetal brain.” Previous studies have found that in the adult brain ALLO activity enhances GABAergic inhibition, producing sedative, anxiolytic, anaesthetic and anticonvulsant effects. And, as the investigators further pointed out, “A large body of evidence suggests that ALLO, through GABAAR signaling, is also a potent regulator of many neurodevelopmental processes …”.

For their newly reported study the researchers created a mouse model in which they were able to selectively decrease the production of ALLO during pregnancy so that some developing mouse pups were exposed to sufficient placental ALLO, while others were not. The results showed that when male and female fetuses were both subjected to ALLO deficiency, the male mice—but not females—showed autism-like behaviors after birth.

Working with collaborators in the U.S., France and Canada, the Penn laboratory analyzed brain development and long-term behavioral outcomes in the offspring. Their studies showed that male offspring that had lacked placental ALLO exposure had structural changes in the cerebellum, a brain region that coordinates movement and has been linked to autism, while their littermates did not. “In particular, we observed thickening of the myelin sheaths, the lipid coating that protects nerve fibers and speeds up neural signaling,” Vacher said. The same type of thickening is also known to occur transiently in the cerebellum of some boys with autism.

The degree of myelin thickening in the juvenile male mice correlated with abnormal behavior, the researchers found. The more the sheath was thickened (as measured by myelin protein levels), the more the male mice exhibited autism-like behaviors, such as decreased sociability and repetitive activities.

“Our experimental model demonstrates that losing placental ALLO alters cerebellar development, including white matter development,” Penn commented. “Cerebellar white matter development occurs primarily after birth, so connecting a change in placental function during pregnancy with lingering impacts on later brain development is a particularly striking result. The findings provide a new way to understand poor placental function. Subtle but important changes during pregnancy or after delivery may set in motion neurodevelopmental disorders that children experience later in life.”

To determine if similar changes might be evident in human infants, the researchers examined post-mortem cerebellar tissues from preterm and full-term infants who had died soon after birth. They found similar changes in brain proteins when comparing cerebellum tissue from male babies born preterm, and male from full-term. “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,” the scientists stated.

The researchers also carried out experiments to investigate the potential therapeutic potential of ALL administration in their preclinical model. They found that the male offspring of mice given a single injection of ALLO in late pregnancy demonstrated fewer autism-like behaviors. Similar results were seen after an injection of muscimol, a drug that enhances the function of GABA receptors—the same receptors that respond to ALLO. Myelin protein levels in the developing cerebellum also normalized with the treatment. “Our study empirically defines a critical role for a specific placental hormone that can alter fetal brain development in late gestation with postnatal developmental consequences,” they concluded. “Our results support the potential therapeutic utility of ALLO administration during gestation if ALLO or its precursors are determined to be low (as might occur with chronic placental insufficiency) but, additionally, suggest the need to maintain fetal ALLO exposure within an appropriate physiological window,” the team noted.

They suggest that understanding both how specific placental hormones shape normal brain development, and how placental loss or dysfunction contributes to the neurological impairments in those born extremely preterm or after compromised pregnancies will lay the groundwork for developing hormone replacement strategies to maintain a normal developmental environment, and prevent long-term impairments in neurobehavior.

Penn further stated, “Identifying when key hormone levels are abnormal, and figuring out how and when to adjust these levels, provides an opportunity to intervene. Performing additional studies with our mouse model, and measuring hormone levels in moms and babies, may lead to earlier treatment to reduce or prevent long-term cognitive and behavioral impairments in high-risk fetuses and newborns.”

“This study is an important first step in understanding how placental hormones may contribute to specific human neurobehavioral outcomes,” said study co-author Vittorio Gallo, PhD, interim chief academic officer at Children’s National Hospital and interim director of the Children’s National Research Institute. “We look forward to continuing our collaboration with Dr. Penn and her team to help define how cerebellar neurons and glia respond to environmental factors, including placental function, that can compromise the developing brain.”

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