Los Angeles, CA - infoZine - Many gene variants have been linked to autism, but how do these subtle changes alter the brain, and
ultimately, behavior?

Using a blend of brain imaging and genetic detective work, scientists at
UCLA's David Geffen School of Medicine and Semel Institute for
Neuroscience and Human Behavior are the first to illustrate how genetic
variants rewire the brain. Published in the Nov. 3 online edition of Science Translational Medicine, their discovery offers the crucial missing physical evidence that links altered genes to modified brain function and learning.

"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."

The UCLA team scrutinized the differences in brain connectivity and
function that result from two forms of the CNTNAP2 gene, one of which
boosts risk for autism.

Earlier studies by Geschwind and others demonstrated that the gene is
most active during brain development in the frontal lobe. The region is
highly involved in learning, which is often disrupted in autistic
children.

Suspecting that CNTNAP2 might influence brain activity, the researchers
used functional magnetic resonance imaging (fMRI) to scan the brains of
32 children as they performed learning-related tasks. Half of the
children had autism, and half did not.

The team's goal was to measure the strength of various communication
pathways in different regions of the brain as they connected with each
other.

The fMRI images excited the scientists – and confirmed their suspicions.

Regardless of their diagnosis, the children carrying the risk variant
showed a disjointed brain. The frontal lobe was over-connected to itself
and poorly connected to the rest of the brain. Communication with the
back of the brain was particularly diminished.

"In children who carry the risk gene, the front of the brain appears to
talk mostly with itself," explained first author Ashley Scott-Van
Zeeland, now a Dickinson Research Fellow at Scripps Translational
Science Institute. "It doesn't communicate as much with other parts of
the brain and lacks long-range connections to the back of the brain."

Depending on which CNTNAP2 version the child carried, the researchers
also observed a difference in connectivity between the left and right
sides of the brain. In most people, the left side processes functions
tied to language, like speech and understanding.

In the children with the non-risk gene, communication pathways in the
frontal lobe linked more strongly to the left side of the brain.

In children with the risk variant, communications pathways in the front
lobe connected more broadly to both sides of the brain. The unusual
symmetry suggests that the gene variant rewires connections in the
brain, perhaps explaining why this version of CNTNAP2 is associated with
delayed speech.

"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," explained co-principal investigator Susan Bookheimer, a professor
of psychiatry who holds the Joaquin Fuster Chair in Cognitive
Neurosciences. "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."

Finding could suggest therapies for rebalancing the brain's circuitry in early development

By enhancing understanding of the relationship between genes, the brain
and behavior, the UCLA finding could lead to earlier detection for
autism, and new interventions to strengthen connections between the
frontal lobe and left side of the brain.

"If we determine that the CNTNAP2 variant is a consistent predictor of
language difficulties," said Scott-Van Zeeland, "we could begin to
design targeted therapies to help rebalance the brain and move it toward
a path of more normal development."

Researchers could test whether specific therapies actually change brain
function by measuring connectivity of patients before and after therapy,
she added.

The authors emphasized that the patterns of connectivity found in the
study still fall along the spectrum of normal gene variation. "One third
of the population carries this variant in its DNA," noted Geschwind.
"It's important to remember that the gene variant alone doesn't cause
autism, it just increases risk."

Led by the UCLA Autism Center of Excellence, the research was supported
by grants from the National Institute of Child Health and Human
Development, National Alliance for Autism Research, National Center for
Research Resources, Autism Speaks, Whitehall Foundation, Training
Program in Neurobehavioral Genetics and a National Research Service
Award.

Other UCLA coauthors included Ana Alvarez-Retuerto, Lisa Sonnenblick,
Jeffrey Rudie, Dara Ghahremani, Jeanette Mumford, Russell Poldrack,
Mirella Dapretto and Brett Abrahams, now at Albert Einstein College of
Medicine.

Source: UCLA