Maternal inflammation during pregnancy increases the number of brain cells in a mouse model of autism. Brain enlargement, a result of this process, is a common feature of autism.
No one knows why, but people with autism-spectrum disorder often experience a period of accelerated brain growth after birth. A new study by UCLA researchers now demonstrates how, in pregnant mice, inflammation — a first line defense of the immune system — can trigger an excessive division of neural stem cells that can cause “overgrowth” in the offspring’s brain.
“We have shown that one way maternal inflammation could result in larger brains and, ultimately, autistic behavior, is through the activation of the neural stem cells that reside in the brain of all developing and adult mammals,” says Harley Kornblum, MD (RES ’91, FEL ’94), PhD, founding director of the Neural Stem Cell Research Center at the Jane and Terry Semel Institute for Neuroscience and Human Behavior at UCLA.
In the study, the researchers injected a pregnant mouse with a low dose of lipopolysaccharide, a toxin found in E. coli bacteria, to mimic environmental factors such as an infection or autoimmune disorder that could activate the immune system. The researchers discovered the toxin caused an excessive production of neural stem cells and enlarged the offsprings’ brains. Notably, the researchers found that mice with enlarged brains also displayed behaviors like those associated with autism in humans. For example, the mice were less likely to vocalize when they were separated from their mother as pups, were less likely to show interest in interacting with other mice, showed increased levels of anxiety and were more likely to engage in repetitive behaviors like excessive grooming.
“Although it’s known that maternal inflammation is a risk factor for some neurodevelopmental disorders such as autism, it’s not thought to directly cause them,” Dr. Kornblum says. He noted that autism is clearly a highly heritable disorder, but other, non-genetic factors clearly play a role.
The researchers also found evidence that the brain growth triggered by the immune reaction was even greater in mice that lacked one copy of a tumor-suppressor gene called phosphatase and tensin homolog, or PTEN. The PTEN protein normally helps prevent cells from growing and dividing too rapidly. In humans, having an abnormal version of the PTEN gene leads to very large head size, or macrocephaly, a condition that also is associated with a high risk for autism. In addition, the team found that the proliferation of neural-stem-cell and brain overgrowth was stimulated by the activation of a specific molecular pathway involving the enzyme NADPH oxidase, which the UCLA researchers have previously found to be associated with neural-stem-cell growth.
“Maternal Inflammation Contributes to Brain Overgrowth and Autism-Associated Behaviors through Altered Redox Signaling in Stem and Progenitor Cells,” Stem Cell Reports, October 9, 2014