Researchers at UCLA have discovered how an autism-risk gene rewires the brain, which could pave the way for treatments aimed at rebalancing brain circuits during early development, according to an article published in Science Translational Medicine. Functional imaging scans have revealed that some of the problems experienced by individuals with autism may be due to too many connections within the frontal lobe of the brain, and poor connections between the frontal lobe and other parts of the brain. The researchers say their discovery, what they described as the result of "a blend of brain imaging and genetic detective work", located the crucial missing mechanisms linking altered genes to changes in brain functions and disrupted learning.
Lead researcher, Neurology and Psychiatry Professor, Dr. Daniel Geschwind, who holds UCLA's Gordon and Virginia MacDonald Distinguished Chair in Human Genetics, said:
This is a key piece of the puzzle we've been searching for. 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.
Dr. Geschwind and team examined the variations in brain function and connectivity resulting from two forms of the CNTNAP2 gene - one form of the gene increases the risk of autism. Geschwind's earlier studies had shown that this gene is much more active during brain development in the frontal lobe. The frontal lobe contains most of the dopamine-sensitive neurons in the cerebral cortex - a system linked to reward, long-term memory, planning, attention and drive - put simply, the frontal lobe is highly involved in learning, which is commonly disrupted in children with autism.
The researchers suspected that CNTNAP2 might have an important impact on brain activity. They used fMRI (functional magnetic resonance imaging) to scan 32 children's brains while they were performing tasks related to learning. Only 16 of them had autism.
Their aim was to gauge the strength of several communication pathways in various parts of the brain as they connected with each other.
The imaging results confirmed their suspicions. All the children with the autism-risk gene showed a disjointed brain, regardless of their diagnosis. Their frontal lobe was over-connected to itself, while connection to the rest of the brain was poor, especially with the back of the brain.
First author, Ashley Scott-Van Zeeland, said:
In children who carry the risk gene, the front of the brain appears to talk mostly with itself. It doesn't communicate as much with other parts of the brain and lacks long-range connections to the back of the brain.
There was also a difference between how the left and right sides of the brain connected with each other, depending on which CNTNAP2 version the child carried.
In the majority of individuals, the left side of the brain deals with functions linked to speech and understanding (language). Children with the non-risk gene were found to have communication pathways in the frontal lobe linked more strongly to the left side of the brain.
However, communication pathways in the front lobe connected more equally to both sides of the brain among children with the risk variant, the scientists wrote. This suggests that the gene variant influences how connections in the brain occur. This could explain why one form of CNTNAP2 is linked to a higher risk of delayed speech.
Co-principal investigator, Psychiatry Professor Susan Bookheimer, who holds UCLA's Joaquin Fuster Chair in Cognitive Neurosciences, said:
We saw that if you had the risk variant, your brain showed disrupted activation patterns whether you were diagnosed on the autism spectrum or not. We suspect that CNTNAP2 plays an important role in wiring neurons at the front of the brain and that the risk variant interferes with that process.
The authors believe their findings could help identify autism risk earlier, and eventually lead to interventions that could enhance connections between the frontal lobe and the left side of the brain.
Scott-Van Zeeland, said:
If we determine that the CNTNAP2 variant is a consistent predictor of language difficulties. we could begin to design targeted therapies to help rebalance the brain and move it toward a path of more normal development.
Clinicians would be able to determine whether treatments had altered brain function effectively by measuring the connectivity of patients before and after certain therapies.
One third of the population carry this variant in its DNA. It's important to remember that the gene variant alone doesn't cause autism, it just increases risk.
The authors concluded:
The convergence between genetic findings and cognitive-behavioral models of autism provides evidence that genetic variation at CNTNAP2 predisposes to diseases such as autism in part through modulation of frontal lobe connectivity.
"Altered Functional Connectivity in Frontal Lobe Circuits Is Associated with Variation in the Autism Risk Gene CNTNAP2"
Ashley A. Scott-Van Zeeland, Brett S. Abrahams, Ana I. Alvarez-Retuerto, Lisa I. Sonnenblick, Jeffrey D. Rudie, Dara Ghahremani, Jeanette A. Mumford, Russell A. Poldrack, Mirella Dapretto, Daniel H. Geschwind and Susan Y. Bookheimer
Sci Transl Med 3 November 2010: Vol. 2, Issue 56, p. 56ra80 DOI: 10.1126/scitranslmed.3001344
Written by Christian Nordqvist