Tuberous sclerosis, commonly associated with autism, is linked to defects in axon guidance
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.