Premature birth has been linked to an increased risk of autism spectrum disorders and other developmental issues, especially in males. The earlier a baby is born, the greater the risk of motor or cognitive deficits. What does the preterm baby miss out on that is so important for long-term outcomes?
A new mouse study suggests that one factor could be the absence of a placental hormone that the developing brain would normally encounter in the second half of pregnancy. The study is the first to show that the absence of a placental hormone affects long-term brain development.
Researchers in the laboratory of Anna Penn, MD, Ph.D., now at Columbia University Vagelos College of Physicians and Surgeons and previously at Children’s National Hospital in Washington, D.C., discovered that lowering levels of a single hormone called allopregnanolone (ALLO) in the placenta caused brain and behavior changes in male offspring that resembled changes seen in some people with autism.
The study also discovered that a single injection of ALLO in late pregnancy could prevent both brain structure and behavioral changes in mice.
“Our study provides new and intriguing insights into how the loss of placental hormones – which occurs 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,” says lead author Claire-Marie Vacher, Ph.D., assistant professor of neonatal sciences in the Department of Pediatrics. “What’s encouraging is that if diagnosed and treated early, these disorders may be preventable.”
The findings were published in the journal Nature Neuroscience online.
A new preclinical study provides the first direct evidence that loss of a placental hormone during pregnancy alters long-term brain development, causing autism-like behaviors in male offspring.
The placenta is an organ that provides oxygen and nutrients to the fetus while also removing waste. It also secretes hormones, including high levels of ALLO in late pregnancy, which may have an impact on brain development. Penn, who is now the L. Stanley James Associate Professor of Pediatrics at Columbia University’s Vagelos College of Physicians and Surgeons and the chief of neonatology at Columbia and NewYork-Presbyterian Morgan Stanley Children’s Hospital, coined the term “neuroplacentology” to describe this new field of research that links placental function to brain development.
One in every ten infants is born prematurely (and thus misses out on normal levels of ALLO and other hormones), and many more pregnancies have poor placental function.
The researchers developed a mouse model in which they were able to selectively decrease ALLO production during pregnancy, exposing some developing pups to sufficient placental ALLO while others were not. Despite the fact that both male and female fetuses were subjected to ALLO deficiency, only male mice displayed autism-like behaviors after birth. The Penn laboratory studied brain development and long-term behavioral outcomes in offspring in collaboration with collaborators in Washington, DC, France, and Canada.
ALLO reduction led to cerebellum changes, autism-like behaviors
Male mice lacking placental ALLO showed structural changes in the cerebellum, a brain region that coordinates movement and has been linked to autism, whereas their littermates did not. “We saw thickening of the myelin sheaths, the lipid coating that protects nerve fibers and speeds up neural signaling,” says Vacher. The same type of thickening has been observed transiently in the cerebellum of some autistic boys.
The researchers also discovered that the degree of myelin thickening in juvenile male mice was related to abnormal behavior. The male mice exhibited autism-like behaviors, such as decreased sociability and repetitive activities, as the sheath thickened (as measured by myelin protein levels).
“Loss of placental ALLO alters cerebellar development, including white matter development, according to our experimental model. Because cerebellar white matter development occurs primarily after birth, linking a change in placental function during pregnancy with long-term effects on brain development is an especially striking finding” Penn says.
“The findings offer a new perspective on poor placental function. Subtle but significant changes during pregnancy or after birth may set in motion neurodevelopmental disorders in children later in life.”
Similarities with human tissue
The researchers also examined post-mortem cerebellar tissues from preterm and full-term infants who died shortly after birth to see if similar changes occur in infants. When cerebellum from male babies born preterm was compared to male full-term babies, these human tissues showed similar changes in brain proteins.
“This research is a critical first step toward understanding how placental hormones may influence specific human neurobehavioral outcomes. We are excited to continue working with Dr. Penn and her team to better understand how cerebellar neurons and glia respond to environmental factors that can harm the developing brain, such as placental function “Vittorio Gallo, PhD, interim chief academic officer at Children’s National Hospital and interim director of the Children’s National Research Institute, is a study co-author.
Hormone injection reduced autism symptoms
The therapeutic potential of ALLO was then evaluated in a preclinical model. The researchers discovered that male offspring of mice given a single injection of ALLO in late pregnancy had fewer autism-like behaviors. Similar findings were obtained following an injection of muscimol, a drug that improves the function of GABA receptors, which are the same receptors that respond to ALLO. The treatment also normalized myelin protein levels in the developing cerebellum.
“Identifying when key hormone levels are abnormal and determining how and when to adjust these levels allows us to intervene,” Penn says. “Further research with our mouse model, as well as hormone levels in mothers and babies, may lead to earlier treatment to reduce or prevent long-term cognitive and behavioral impairments in high-risk fetuses and newborns.”