New research points to brain connectivity defect in autism

Kathleen Blanchard's picture

New research shows that abnormal connectivity in the way the brain is wired occurs with autism. The inability to process brain signals properly, causing an interruption of the flow of information, is discovered by researchers at Children's Hospital Boston who studied individuals with tuberous sclerosis complex (TSC). Twenty to twenty five percent of individuals with TSC also have autism spectrum disorder.

According to Mustafa Sahin, MD, PhD, of Children's Department of Neurology, "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. 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."

The researchers discovered that a gene that leads to TSC, known as TSC2, also plays a role in scrambling connections in the developing brain by preventing growing nerve fibers (axons) from finding their proper destination. The researchers, through further exploration, speculate that abnormal wiring in the part of the brain that involves social cognition may be present in individuals with autism.


Mice deficient in TSC2 could not navigate, indicating a loss of brain connection between the retina of the eye and the visual area of the brain. The tips of axons, known as “growth cones” failed to respond to molecules known as 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. Next the researchers found activation of a molecular pathway called mTOR that occurred in response to loss of responsiveness of ephrins. Many of the signals between the retina and brain were not getting through in the mice studied, deficient in TSC2. The researchers feel their findings have overall relevance for brain development. In autism, the researchers suspect abnormal brain connectivity is related to social cognition from the same pathways.

"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."

Identification of the connection pathway in the brain opens the door for treatment options of autism and other neurodevelopmental disorders. By blocking the abnormal pathways with the medication rapamycin, the scientists were able to reverse changes in the brain that result in connectivity defects seen with autism.

Nature Neuroscience, Jan. 2010: “Tsc2-Rheb signaling regulates EphA-mediated axon guidance"