Research ArticlesAutism

Altered Functional Connectivity in Frontal Lobe Circuits Is Associated with Variation in the Autism Risk Gene CNTNAP2

Science Translational Medicine  03 Nov 2010:
Vol. 2, Issue 56, pp. 56ra80
DOI: 10.1126/scitranslmed.3001344

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A Window into the Genetic Control of Brain Function

Even seemingly simple traits like height are controlled by more than 180 separate genes. Imagine the complexity of the genetic network that determines the structure of the human brain: Billions of neurons connected to one another by at least as many axons. Variations in these links lead to differences among us and, sometimes, to disability, but picking out the key connections is not easy. Now, Scott-van Zeeland and colleagues show that the two versions of a protein that guides growth of the prefrontal cortex—one of which is known to confer risk of autism—generate distinct neural circuits in this region of the brain, possibly explaining the increased risk of autism and other intellectual disabilities in carriers.

The protein is contactin-associated protein-like 2 (CNTNAP2), which has turned up in a number of genetic studies as associated with autism and other language-related disorders. Caspr2, the protein encoded by CNTNAP2, participates in cellular migration and in forming the final layered organization of the brain. It is expressed during development in the frontal and temporal lobes, including the frontal cortex and stratum, areas that participate in language and learning. The authors of this study have used functional magnetic resonance imaging (fMRI) of the brain to pinpoint the differences in brain structure and function that result from two variants of CNTNAP2, one of which confers risk of autism. They found in a discovery and a replication cohort of children that carriers of the risky allele showed more neural activity in the medial prefrontal cortex as they performed an assigned task. Moreover, this region was connected only locally in a diffuse bilateral network in the carriers, whereas in those with the nonrisk allele the medial prefrontal cortex conveyed information to more posterior regions via a network on the left side.

This left lateralized functional anterior-posterior connection in the noncarriers involves regions of the brain known to control language processing, a skill that is defective in some people with autism. It is possible that the lack of efficient information transfer to these regions from frontal areas in the risk allele–carrying children may contribute to the increased chance that they will be affected by autism or other related disorders. The careful dissection of genetic contributions to discrete aspects of brain structure and function (so-called endophenotypes) such as reported here is one way to begin to untangle the basis of human-to-human variations in cognition and behavior.


  • * Present address: Departments of Genetics and Neuroscience, Price Center for Genetic and Translational Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

  • These authors co-supervised this work.

  • Citation: A. A. Scott-Van Zeeland, B. S. Abrahams, A. I. Alvarez-Retuerto, L. I. Sonnenblick, J. D. Rudie, D. Ghahremani, J. A. Mumford, R. A. Poldrack, M. Dapretto, D. H. Geschwind, S. Y. Bookheimer, Altered Functional Connectivity in Frontal Lobe Circuits Is Associated with Variation in the Autism Risk Gene CNTNAP2. Sci. Transl. Med. 2, 56ra80 (2010).