Mutations Discovered in Autism Risk Gene That Alter Brain Development

Scientists at The Scripps Research Institute, also known as TSRI, have uncovered mutations in a specific autism risk gene, and these mutations alter the basic trajectory of early brain development in animal models.

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Way back in 1943, autism was described by psychiatrist Leo Kanner, and reports were back then that some children with autism spectrum disorder have enlarged heads. While we have made some progress in autism and autism spectrum disorder since then, we still have not really figured out why there is abnormal growth in the head and brain in some people with the disorder. This new study however, which was published in the Journal of Neuroscience, might be getting closer to answering this important question about the head and brain of some people with autism. This new study focused on the gene PTEN, which has a mutation in about 20 percent of people who have autism spectrum disorder and enlarged heads, which is known as macrocephaly.

The new research was led by Damon Page, who is a biologist at Scripps in Florida. Page found that the mutations in PTEN, which approximate the ones found in a subgroup of people with autism spectrum disorder, lead to changed in the number of two important cell types that make up the brain. These two cell types are known as -neurons and glia. During birth, the neurons are more abundant than normal, and in adulthood, the number of neurons in the brains of mutant animals is basically normal. The glia, which is supporting the neurons actually become over-represented. Page said that “In the adult brain, excess glia are a primary cause of the overall change in brain size.” He went onto say that “This raises the intriguing possibility that these excess glia may, in fact, contribute to abnormal development and function of brain circuitry when PTEN is mutated.”

The research team observed the brain overgrowth in the PTEN using mice, and the study showed that the increase in size occurred at birth and then again as an adult. During the early juvenile period of life in the mice, the increase happened the least. The researchers noted that the abnormal pattern of growth seemed to be caused by an amplification of the normal brain development process, and during this time the neurons are generated in an over-abundance before birth. The glia are generated after the neurons, and then there is a process of cell death that trims off the over-abundance. The process of cell death is known as apoptosis, which is a natural phenomenon that removes unnecessary neurons during normal brain development periods. The first author of the study was Research Associate Youjun Chen, and he said “We find it very striking that in the brains of PTEN mutant mice, the presence of excess neurons is corrected by excessive apoptosis. After that, excess glia are made. In adulthood, the number of glial cells increases by more than 20 percent in our models.”

What happened was that the researchers were able to trace the effects back to an increase in signaling that is done through a molecule known as beta Catenin. Both the PTEN and beta Catenin are important to help control growth in the developing brain, and this happens in humans and in mice. These two work together to make a common pathway to help regulate the brain growth trajectory, which happens by controlling the number and types of cells being produced. This means that an imbalance in the relationship between the two could wind up contributing to an abnormal brain growth in a certain group of people who have autism spectrum disorder. Autism spectrum disorder affects about 1 percent of the total population, and about 80 percent of all diagnosed are males. Page noted that the mice are still mostly able to adapt at the level of behavior, even with the effects of the PTEN mutation on brain growth. The only ways that the mice were not able to adapt were related to social behaviors and other types of behaviors that are related to autism spectrum disorder.

Essentially, this study is showing that the brain tries really hard to compensate for the abnormal growth in the brain, and how well someone can adapt might shape their outcome in terms of cognition and behavior. The ability to adapt to the brain growth can be influenced by a number of factors including genetics or environmental factors. The study also shows that both mice and humans are pretty resilient when it comes to trying to overcome obstacles in life, and where one part of the brain might be over producing, other parts of the brain are trying to level out the playing field, which then helps the person adapt to their abnormal growth patterns. This study is one of the first studies to really show why some people with autism spectrum disorder have enlarged brains and heads, and more research will likely be done to find more information about how this process works.