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Spectrum: Autism Research News

Studies on 22q11.2 region link genes, circuits, behavior

by  /  10 November 2013
THIS ARTICLE IS MORE THAN FIVE YEARS OLD

This article is more than five years old. Autism research — and science in general — is constantly evolving, so older articles may contain information or theories that have been reevaluated since their original publication date.

Number game: Deletions in the 22q11.2 chromosomal region disrupt the production of new neurons, leaving the mouse embryonic cortex thin and depopulated (right) compared with controls (left).

Deletion of a gene in 22q11.2, a chromosomal region linked to autism and schizophrenia, leads to small head size in mice, according to research presented Saturday at the 2013 Society for Neuroscience annual meeting in San Diego.

The same team also found that deletion of a larger section of the region, which spans about 40 genes, disrupts brain connections in the mice. The more disruptions the mice show, the more they struggle with learning and memory.

Both sets of mice also show a decrease in the production of brain cells in certain areas of the cortex, according to results presented in two posters.

“We can connect the dots from genes to development to behavior,” says lead investigator Anthony-Samuel LaMantia, professor of pharmacology and physiology at George Washington University in Washington, D.C. “This has never been done before.”

The researchers suggested a mechanism driving this connection: Deletions in the 22q11.2 region slow cell proliferation in the cortex, in turn upsetting the integrity of connections in the brain and ultimately affecting the mice’s cognitive abilities.

“For decades, there has been this idea that these disorders of higher cognitive function, social cognition and behavior — autism, intellectual disability, schizophrenia, the whole list — reflect disruption of the organization of the brain, particularly disruption of the cerebral cortex,” says LaMantia. “The only problem is that nobody has been able to show that.”

Full spectrum:

The lab chose to focus on the 22q11.2 deletion because it is common, is involved in a full spectrum of disorders, and the genes line up in people and mice, so that the mouse models are good representatives of the disorders in people.

The researchers focused in particular on RANBP1, a gene in this region that is known to be involved in regulating the cell cycle.

While the mice were still in utero, the researchers knocked out the gene, which is extremely sensitive to vitamin A, using high doses of the vitamin. Loss of the gene causes 60 percent of the mice to grow a brain outside the skull that then shrivels. The rest have brains that are noticeably smaller than those of controls.

It turns out that the cortex in these mice has fewer neurons. Cells called basal progenitors, which are designed to boost the population of stem cells, also divide less often than in controls.

That small decrease in the basal progenitors’ proliferation translates to a diminished brain and disrupted circuits later on in the mice’s development.

“As a null, [RANBP1] definitely is destroying the ability to make a proper cortex,” says Thomas Maynard, associate research professor of pharmacology and physiology at George Washington University, who presented the work.

Children with the 22q11.2 deletion have one good copy of the gene, however, so the observations in mice may not fully explain the children’s symptoms, he says.

These children have difficulty with attention, working memory and other cognitive functions. The researchers found that mice lacking one copy of the region also show trouble with a learning task.

In the task, mice have to learn to touch a screen to choose a pattern of horizontal or vertical lines for the reward of a drop of strawberry milkshake. Once a mouse learns the rewarding pattern, the researchers switch the reward to the other pattern. Control mice adjust to learn the new pattern, but mice with the deletion find it difficult to do so. 

Daniel Meechan, a research scientist in LaMantia’s lab, found that mice with the 22q11.2 deletion have fewer of a subset of cells called projection neurons than controls do. These neurons project long axons to other sites in the frontal cortex or in other parts of the brain.

“The idea would be that if there’s [fewer] projection neurons, then they’re probably projecting less to their normal distant targets,” says Meechan. What’s more, the weaker the connectivity, the worse the mice perform on the test. This in turn seems to correlate with the decrease in the number of neurons in the cortex and the thinness of the layers there.  

“I’m not aware of any other studies that have closed the loop from embryonic development to behavioral phenotypes in the mature cortex,” says Meechan.

For more reports from the 2013 Society for Neuroscience annual meeting, please click here.