JUPITER, FL — Scientists at Scripps Research have shed new light on a genetic mutation that is clearly linked with autism spectrum disorders; in so doing they have highlighted a potential pathway for early treatment.
Mutations in a gene known as PTEN—one of the most extensively validated in autism genetics studies—can lead to the disproportional overgrowth of nerve fiber tracts that convey information between brain regions, according to the Scripps Research imaging study of mice that carry the mutation.
The research, published in Translational Psychiatry, points to the likelihood that this abnormal and uneven brain growth is caused by an excess of support cells in the brain, known as glia, during early development. The researchers suspect that such effects might be largely preventable with early drug treatments, thereby correcting the most prominent brain abnormality found in individuals with PTEN mutations and autism.
“These findings suggest that, in principle, one could use brain imaging, together with genetic testing, to detect this syndrome in infants when there is still time for useful intervention,” says the study’s senior author Damon Page, PhD, associate professor in the Department of Neuroscience at Scripps Research.
The U.S. Centers for Disease Control and Prevention estimates that autism spectrum disorders (ASDs) now affect one in every 37 boys and one in every 151 girls in the country. These disorders are largely genetic, though no one gene mutation dominates. Instead, it appears that ASDs can result from mutations in any of hundreds of different genes, each of which accounts for only a tiny subset of ASD cases. PTEN is among the most studied of these risk genes.
Mutations that inactivate one copy of the PTEN gene can cause autism as well as “macrocephaly”—the overgrowth of the brain and head—in both humans and lab mice. Moreover, the molecular signaling pathways affected by the reduction in PTEN activity are known to be disrupted in about 5 percent of ASD cases, including cases without PTEN mutations. Scientists therefore hope that studying PTEN mutations will yield important clues about the causes of autism and good strategies for treating it.
One problem researchers face as they pursue this line of investigation is how to record the development of abnormal brain growth in children with PTEN mutations, particularly very young children, given the need for MRI imaging and the fact that PTEN-associated autism often isn’t diagnosed before age 2. To get around that problem, Page and his team in this study used MRI to image the brains of mice with mutations in the mouse version of PTEN, one week after birth—the developmental equivalent of birth in humans—and then again in early adulthood.
They found that adult mice with the mutation show a pattern of abnormal brain growth—higher in multiple areas, lower in one or two others including the forebrain—very much like that seen in humans who have PTEN mutations and autism. Yet they also found that week-old mutant mice do not show this same pattern; instead they show considerable variability in growth abnormalities across different brain regions. Moreover, the brains of the mutant mice at this early stage are only moderately different than normal mouse brains. Both of these findings hint that a treatment for humans with PTEN mutations, if it were available, could prevent much of the usual brain overgrowth/undergrowth and autism signs if delivered shortly after birth.
The scientists observed that the most prominent feature of abnormal brain growth in adult mutant mice, a feature seen also in the few imaging studies of people with PTEN mutations, is the overgrowth of “white matter”—the bundles of nerve fibers that, like fiber-optic internet cables, connect different brain regions. Researchers have suspected that this PTEN-related overgrowth of white matter is largely the result of an abnormally thick sheathing of nerve fibers by a substance called myelin—and Page and colleagues were able to confirm that the myelinated tracts of adult mutant mice are abnormally thickened.
The team found as well that in the brains of these mice just a week after birth, support cells called glia, which make up myelin, are proliferating more than usual—and likely account for the white matter overgrowth that soon develops. This finding suggested a target for treatment.
“We found that we were able to reverse this glial cell over-proliferation in lab dish cultures with a naturally occurring variant of the mouse Pten protein that can enter cells and make up for the missing copy of the gene in our mutant mice,” says Amy Clipperton-Allen, PhD, a postdoctoral research associate in Page’s lab who was co-lead author of the study and performed most of the experiments.
Adding an enzyme-inhibiting compound that duplicates one of PTEN’s key activities in cells also reversed the glial cell over-proliferation, the researchers found.
The scientists now plan to do further studies to find compounds that could have a similar effect at reducing glial cell over-proliferation but would be more suitable for development into drugs. They are also following up with studies in the mutant mice of how overgrowth in different brain regions correlates with different autism-like behaviors.
“Knowing how the abnormal scaling of brain areas relates to the behavioral symptoms of autism could give us a way improve diagnosis in early childhood, and hopefully intervene early with drug treatments as these are developed,” Page says.
The other co-authors of the study, “Pten haploinsufficiency disrupts scaling across brain areas during development in mice,” were Ori Cohen PhD, Massimiliano Aceti PhD, Aya Zucca, and Jenna Levy, of Scripps Research; and Jacob Ellegood PhD and Jason Lerch, PhD of the Hospital for Sick Children in Toronto.
Support for the research was provided by the National Institutes of Health (R01MH105610 and R01MH108519) and gift funds from Ms. Nancy Lurie Marks.