Studying a rare disorder known as tuberous sclerosis complex (TSC), researchers at Children's Hospital Boston add to a growing body of evidence suggesting that autism spectrum disorders, which affect 25 to 50 percent of TSC patients, result from a miswiring of connections in the developing brain, leading to improper information flow.
The finding may also help explain why many people with TSC have seizures and intellectual disabilities. Findings were published online in Nature Neuroscience on January 10.
TSC causes benign tumors throughout the body, including the brain. But patients with TSC may have autism, epilepsy or intellectual disabilities even in the absence of these growths. Now, researchers led by Mustafa Sahin, MD, PhD, of Children's Department of Neurology, provide evidence that mutations in one of the TSC's causative genes, known as TSC2, prevent growing nerve fibers (axons) from finding their proper destinations in the developing brain.
Studying a well-characterized axon route – between the eye's retina and the visual area of the brain – Sahin and colleagues showed that when mouse neurons were deficient in TSC2, their axons failed to land in the right places. Further investigation showed that the axons' tips, known as "growth cones," did not respond to navigation cues from a group of molecules called ephrins. "Normally ephrins cause growth cones to collapse in neurons, but in tuberous sclerosis the axons don't heed these repulsive cues, so keep growing," says Sahin, the study's senior investigator.
Additional experiments indicated that the loss of responsiveness to ephrin signals resulted from activation of a molecular pathway called mTOR, whose activity increased when neurons were deficient in TSC2. Axon tracing in the mice showed that many axons originating in the retina were not mapping to the expected part of the brain.
Although the study looked only at retinal connections to the brain, the researchers believe their findings may have general relevance for the organization of the developing brain. Scientists speculate that in autism, wiring may be abnormal in the areas of the brain involved in social cognition.
"People have started to look at autism as a developmental disconnection syndrome – there are either too many connections or too few connections between different parts of the brain," says Sahin. "In the mouse models, we're seeing an exuberance of connections, consistent with the idea that autism may involve a sensory overload, and/or a lack of filtering of information."
Sahin hopes that the brain's miswiring can be corrected by drugs targeting the molecular pathways that cause it. The mTOR pathway is emerging as central to various kinds of axon abnormalities, and drugs inhibiting mTOR has already been approved by the FDA. For example, one mTOR inhibitor, rapamycin, is currently used mainly to prevent organ rejection in transplant patients, and Sahin plans to launch a clinical trial of a rapamycin-like drug in approximately 50 patients with TSC later this year, to see if the drug improves neurocognition, autism and seizures.
In 2008, Sahin and colleagues published related research in Genes & Development showing that when TSC1 and TSC2 are inactivated, brain cells grow more than one axon – an abnormal configuration that exacerbates abnormal brain connectivity. The mTOR pathway was, again, shown to be involved, and when it was inhibited with rapamycin, neurons grew normally, sprouting just one axon.
Supporting the mouse data, a study by Sahin and his colleague Simon Warfield, PhD, in the Computational Radiology Laboratory at Children's, examined the brains of 10 patients with TSC, 7 of whom also had autism or developmental delay, and 6 unaffected controls. Using an advanced kind of MRI imaging called diffusion tensor imaging, they documented disorganized and structurally abnormal tracts of axons in the TSC group, particularly in the visual and social cognition areas of the brain (see image). The axons also were poorly myelinated – their fatty coating, which helps axons conduct electrical signals, was compromised. (In other studies, done in collaboration with David Kwiatkowski at Brigham and Women's Hospital, giving rapamycin normalized myelination in mice.)
Sahin has also been studying additional genes previously found to be deleted or duplicated in patients with autism, and finding that deletion of some of them causes neurons to produce multiple axons – an abnormality that, again, appears to be reversed with rapamycin.
"Many of the genes implicated in autism may possibly converge on a few common pathways controlling the wiring of nerve cells," says Sahin. "Rare genetic disorders like TSC are providing us with vital clues about brain mechanisms leading to autism spectrum disorders. Understanding the neurobiology of these disorders is likely to lead to new treatment options not only for TSC patients, but also for patients with other neurodevelopmental diseases caused by defective myelination and connectivity, such as autism, epilepsy and intellectual disability."
The current study, titled "Tsc2-Rheb signaling regulates EphA-mediated axon guidance," was funded by grants from the National Institutes of Health, the John Merck Scholars Fund, Tuberous Sclerosis Alliance, the Manton Foundation, the Children's Hospital Boston Translational Research Program, and the Children's Hospital Boston Mental Retardation and Developmental Disabilities Research Center.
Duyu Nie was first author on the paper. Coauthors were Duyu Nie, Alessia Di Nardo, Juliette M Han, Hasani Baharanyi, Ioannis Kramvis, and ThanhThao Huynh, all of the F.M. Kirby Neurobiology Center and Department of Neurology, Children's Hospital Boston; Sandra Dabora of Brigham and Women's Hospital; Simone Codeluppi and Elena B Pasquale of the Burnham Institute for Medical Research, and University of California San Diego; and Pier Paolo Pandolfi of Beth Israel Deaconess Cancer Center.
Children's Hospital Boston is home to the world's largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 500 scientists, including eight members of the National Academy of Sciences, 13 members of the Institute of Medicine and 12 members of the Howard Hughes Medical Institute comprise Children's research community. Founded as a 20-bed hospital for children, Children's Hospital Boston today is a 396-bed comprehensive center for pediatric and adolescent health care grounded in the values of excellence in patient care and sensitivity to the complex needs and diversity of children and families. Children's also is the primary pediatric teaching affiliate of Harvard Medical School.
James Newton | EurekAlert!
Hot cars can hit deadly temperatures in as little as one hour
24.05.2018 | Arizona State University
3D images of cancer cells in the body: Medical physicists from Halle present new method
16.05.2018 | Martin-Luther-Universität Halle-Wittenberg
The more electronics steer, accelerate and brake cars, the more important it is to protect them against cyber-attacks. That is why 15 partners from industry and academia will work together over the next three years on new approaches to IT security in self-driving cars. The joint project goes by the name Security For Connected, Autonomous Cars (SecForCARs) and has funding of €7.2 million from the German Federal Ministry of Education and Research. Infineon is leading the project.
Vehicles already offer diverse communication interfaces and more and more automated functions, such as distance and lane-keeping assist systems. At the same...
A research team led by physicists at the Technical University of Munich (TUM) has developed molecular nanoswitches that can be toggled between two structurally different states using an applied voltage. They can serve as the basis for a pioneering class of devices that could replace silicon-based components with organic molecules.
The development of new electronic technologies drives the incessant reduction of functional component sizes. In the context of an international collaborative...
At the LASYS 2018, from June 5th to 7th, the Laser Zentrum Hannover e.V. (LZH) will be showcasing processes for the laser material processing of tomorrow in hall 4 at stand 4E75. With blown bomb shells the LZH will present first results of a research project on civil security.
At this year's LASYS, the LZH will exhibit light-based processes such as cutting, welding, ablation and structuring as well as additive manufacturing for...
There are videos on the internet that can make one marvel at technology. For example, a smartphone is casually bent around the arm or a thin-film display is rolled in all directions and with almost every diameter. From the user's point of view, this looks fantastic. From a professional point of view, however, the question arises: Is that already possible?
At Display Week 2018, scientists from the Fraunhofer Institute for Applied Polymer Research IAP will be demonstrating today’s technological possibilities and...
So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics
Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...
25.05.2018 | Event News
02.05.2018 | Event News
13.04.2018 | Event News
25.05.2018 | Event News
25.05.2018 | Machine Engineering
25.05.2018 | Life Sciences