The underlying physiological causes of autism continue to remain a mystery, but new research is helping to narrow down the field. Scientists at Children’s Hospital Boston have been studying the brains of humans and mice with tuberous sclerosis complex, a rare disorder related to autism, and have discovered that during axon formation the nerve fibers seem to have difficulty in finding correct connection points to link to in the brain.
Studying a well-characterized axon route–between the eye’s retina and the visual area of the brain–Sahin [Mustafa Sahin, MD, PhD, of Children’s Department of Neurology] 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.”
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.
Image: Diffusion tensor images of the brain illustrate the disorganization of nerve fibers in a 17-year-old girl with tuberous sclerosis complex (TSC) and autism as compared with a healthy girl of the same age. In the affected girl, the tracts of nerves that carry information from the brain’s thalamus to the visual cortex are less organized, with far fewer axons connecting to the cortex. The brighter colors in the healthy brain illustrate greater structural integrity of the tracts. Courtesy Simon Warfield, PhD
Press release: Research adds to evidence that autism is a brain ‘connectivity’ disorder
Abstract in Nature Neuroscience: Tsc2-Rheb signaling regulates EphA-mediated axon guidance