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Research: Autism a ‘connectivity’ disorder
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Studying a disorder known as tuberous sclerosis complex, researchers at Children’s Hospital Boston add to a growing body of evidence suggesting that autism spectrum disorders result from a miswiring of connections in the developing brain.
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. Researchers led by Mustafa Sahin, MD, of the Children’s Department of Neurology, note in their study that mutations in one of the TSC’s causative genes, known as TSC2, prevent growing 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 — researchers showed that when mouse neurons were deficient in TSC2, their axons failed to land in the right places.
Although the study looked only at retinal connections to the brain, the researchers said their findings may have general relevance for the developing brain.
“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,” Sahin said in a press release. “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. – by Colleen Zacharyczuk
For more information:
- Glessner JT. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature. 2009;459:569-573.
- Minshew NJ. The new neurobiology of autism. Arch Neurol. 2007;64:945-950.
- Nature Neuroscience. 2010; doi:10.1038/nn.2477
- Nie. Tsc2-Rheb signaling regulates EphA-mediated axon guidance. Nature Neuroscience. 2010;doi:10.1038/nn.2477
- Wang K. Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature. 2009;459:528-533.
The possibility that a fundamental problem of intrahemispheric cortical underconnectivity may underlie many of the deficits associated with autism spectrum disorders is suggested by functional magnetic resonance imaging (fMRI) studies documenting diminished functional connectivity among cortical regions involved in language, executive functioning, and social cognition. Other supporting evidence comes from structural magnetic resonance imaging (MRI) morphometry and diffusion tensor imaging (DTI) studies demonstrating regional differences in white matter volume and histopathological studies showing abnormalities in cortical minicolumns. Although the mechanisms responsible for structural and functional underconnectivity are not clear, abnormalities involving genes coding for neuronal cell-adhesion molecules may confer increased autism susceptibility by causing cell-adhesion problems that disrupt axonal guidance, synaptic formation and plasticity and neuronal-glial interactions.
TSC caused by mutations in the genes TSC1 or TSC2, is often associated with clinical findings including epilepsy, intellectual disability, and autism spectrum disorders, even in the absence of cortical tubers. Nie and colleagues have identified a mechanism by which Tsc2 regulates ephrin-A-mediated axonal guidance and haploinsufficiency results in aberrant retinogeniculate projections in the mouse visual system. Information released by Children’s Hospital Boston states that additional work by the corresponding author, Sahin, and Dr. Simon Warfield documents disorganized and structurally abnormal tracts of axons by DTI in a small group of individuals with TSC and autism or developmental delay as compared to controls, although, to my knowledge, these data are unpublished. Disruption of axonal guidance may be a common pathway by which a number of different genes, including TSC2, can cause abnormalities of neural connectivity. The specificity of this finding to autism is unclear, and it may be a mechanism in intellectual disability without autism as well.
– Scott M. Myers, MD
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