Placental hormone loss spurs autism-like traits in mice | Spectrum
My oh myelin: In a new mouse model of autism, the males have an unusually thick myelin in the cerebellum, which correlates with more intense autism-like features.
Male mice exposed to atypically low levels of a placental hormone in the womb have altered brain development and anti-social behavior, according to a new study. The results could help explain why premature birth – which coincides with a lack of placenta hormones – is linked to an increased likelihood of autism.
The hormone called allopregnanolone penetrates the blood-brain barrier, binds to receptors for the chemical messenger substance gamma-aminobutyric acid (GABA) and helps regulate aspects of neuronal development, including the growth of new neurons. Its concentrations typically reach the fetus during the second half of pregnancy.
In the new study, researchers constructed a mouse model with low fetal allopregnanolone levels, mimicking the loss of the hormone due to premature birth or placental dysfunction. In particular, the male mice show structural changes in the cerebellum, a brain region known for balance and motor control, and show more pronounced autism-like features than control mice or female model mice.
The new model “has good translational potential for understanding the underlying mechanisms of gender differences in neurodevelopmental disorders such as autism,” says Amanda Kentner, professor of psychology at the Massachusetts College of Pharmacy and Health Sciences in Boston, who is not involved in the study was work.
Injecting allopregnanolone into a pregnant mouse while pregnant reduced the likelihood that their offspring would have autism-like characteristics, the researchers found.
Though preliminary, the result suggests possible treatment of babies with low hormone levels, says study researcher Anna Penn, professor of pediatrics at Columbia University.
Penn and her colleagues only caused the hormone deficiency in a few mice in one litter by deleting the gene that synthesizes allopregnanolone from fetal cells that develop into the placenta.
“With this model, both model and wild type animals could be carried and raised by the same mother mouse,” says Kentner. “Apart from the presence or absence of the gene, the fetal and postnatal environments would presumably otherwise be identical.”
Animals lacking the gene had less allopregnanolone in their brains, the researchers confirmed. They also had atypical gene expression throughout the brain, as revealed by RNA sequencing – with the highest number of differentially expressed genes in the male cerebellum. Many of these genes are involved in myelination, the process of isolating axon fibers in a sheath that improves signal conduction between neurons.
Compared to control mice and female model mice, the male model mice had thicker myelin sheaths and fewer non-myelinated axons in the cerebellum, the team found. As embryos, the male model mice also produced more cells that develop into oligodendrocytes, the cells that produce myelin. And postnatally, these cells continued to mature unusually quickly.
“We can’t explain that today,” says study director Claire-Marie Vacher, assistant professor of pediatrics at Columbia University. In a separate dataset, she and her colleagues saw similar patterns of increased myelination and increased production of oligodendrocytes in premature infants – suggesting that the same mechanisms are at play.
Since the cerebellum is essential for the coordination of movements, the researchers next tested the motor skills of the model animals with a rotating stick.
The male model mice held their balance on the bar longer than the control mice, the team found. Several other autism mouse models also do surprisingly well on this test.
When Penn and her colleagues examined the behavior of the animals, they found that many of the male model mice exhibited characteristics similar to autism, including repetitive behaviors and a preference for objects over other mice.
Male model mice also made fewer ultrasound vocalizations than female and control mice. This trait could indicate atypical communication, but it could also have influenced the parental care the model mice received, further influencing their developmental course and possibly falsifying the results, says Kentner.
The model mice scored higher than the controls on a composite measure of trait severity, the team found, and those with the greatest increases in white matter had the highest grades.
“It gives you a lot of confidence that [the hormone levels] are not strange deviations, ”but rather play a major role in the autism-like traits observed, says Emanuel DiCicco-Bloom, professor of neuroscience and cell biology and pediatrics at Rutgers University in Piscataway, New Jersey. DiCicco-Bloom was not involved in the study.
Female model mice appear to have atypical brain development in the cortex and different behavioral changes than the males – data the researchers want to publish soon, says Penn.
“It indicates that there are indeed regional changes that the [sex] Differences. And that could point to different types of interventions that could be helpful in aligning behavioral therapies and teaching, as well as what types of early stage and preventive therapies might work in boys versus girls, “says Penn.
It also means that “we may need to redefine autism in girls,” says Vacher. She and her colleagues were able to identify autism-like behaviors in the male model mice because they specifically searched for them, she says, but specific female traits can go unnoticed until they are better defined.
Quote this article: https://doi.org/10.53053/CBLX5696