Science Translational Medicine: Front-Brain Activity Tied to Genetics, Autism

The language and cognitive difficulties often seen in autism may be caused in part by an overly connected frontal lobe within the brain, says a new study of children published in Science Translational Medicine.

The research points to a gene called CNTNAP2 as responsible for wiring neurons in the front of the brain. If carrying different versions of CNTNAP2 is found to be a consistent predictor of language difficulties, the findings may help researchers design targeted therapies to assist the brain toward a path of more normative development early on.

 

Functional connectivity maps for the Discovery (top panel), Replication (middle panel) and Combined (bottom panel) samples. Non-risk carriers are shown on the top rows and Risk carriers are on the bottom rows of each panel. The maps show much greater connectivity within the frontal lobe for Risk carriers compared to Non-Risk carriers. This pattern was observed in two independent sets of children (autism and typically developing controls), indicating that this common gene variant is related to the spectrum of normal brain function. Images were rendered using CARET (http://brainmap.wustl.edu/caret). [Image © Science/AAAS]

Functional connectivity maps for the Discovery (top panel), Replication (middle panel) and Combined (bottom panel) samples. Non-risk carriers are shown on the top rows and Risk carriers are on the bottom rows of each panel. The maps show much greater connectivity within the frontal lobe for Risk carriers compared to Non-Risk carriers. This pattern was observed in two independent sets of children (autism and typically developing controls), indicating that this common gene variant is related to the spectrum of normal brain function. Images were rendered using CARET (http://brainmap.wustl.edu/caret).
[Image © Science/AAAS]

“This is a key piece of the puzzle we’ve been searching for,” said co-principal investigator Dr. Daniel Geschwind, a professor of neurology and psychiatry who holds UCLA’s Gordon and Virginia MacDonald Distinguished Chair in Human Genetics. “Now we can begin to unravel the mystery of how genes rearrange the brain’s circuitry, not only in autism but in many related neurological disorders.”

 

It’s important to note that the patterns of frontal lobe connectivity found in this study are part of the spectrum of normal gene variation. As such, merely carrying the risk gene isn’t enough to be diagnosed with autism or intellectual disability, the authors say.

Autism and other complex neurodevelopmental disorders are likely caused by the combination of many genes, so while this particular risk version of the CNTNAP2 gene may steer the brain towards more frontal lobe connections, there are many other genes that are needed to cause the full disease.

Scanning the brains of a group of children, Daniel Geschwind and colleagues at UCLA pinpointed the differences in brain connectivity and function that result from two variants of the CNTNAP2 gene, one of which confers risk of autism. CNTNAP2 is normally expressed during development in the frontal and temporal lobes of the brain—areas known to be involved in language and learning.

The brain scans of children carrying the risk gene revealed a disjointed brain, meaning that the frontal lobe is not properly connected to the rest of the brain, and over-connected to itself. As a result, the frontal lobe “talks to itself” more than it talks to other regions of the brain, and lacks longer-range connections to the back of the brain.

This pattern of increased frontal brain connectivity is linked to differences in the DNA sequence of the CNTNAP2 gene, the team found. Another interesting finding related to this gene is the difference in connectivity between the left and right sides of the brain, depending on which version of CNTNAP2 study participants carried.

The left side of the brain is typically associated with language functions like speaking and comprehension. The authors found that in the children who carried the non-risk version of CNTNAP2, the frontal lobe region preferentially linked up to the left side of the brain. In contrast, in children who carried the risk version of the gene, the frontal lobe connected to both the right and left sides.

Links

Read the abstract for “Front-Brain Activity Tied to Genetics, Autism.”