Article: Brain connectivity and autism

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ScienceDaily (Jan. 11, 2010) — 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 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 was funded by grants from the National Institutes of Health,

the 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, tte 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; 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.

 

 

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