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Rewriting Life

Mapping Genetic Abnormalities in Autism

New tools could uncover subtle changes.

A new project to study the brains of people with autism in unprecedented detail could finally pinpoint subtle neurological changes that underlie the disorder. Researchers will use an innovative set of tools developed to study gene expression to analyze exactly where early brain development goes awry.

Genes and the Brain: Shown here is a computationally reconstructed 3-D rendering of a mouse brain illustrating the expression of a particular gene, Tmem16b. The translucent forms represent the left half of the brain. The spheres illustrate the area in the brain where the gene has been turned on, while the color of the spheres indicates the relative degree of expression. (Red and orange indicate the highest expression levels.) Scientists will use similar tools to study brain tissue from children with autism. The image was generated from the Allen Brain Atlas Brain Explorer.

“The technology now exists to be able to examine in fine detail the organization of brain cells–for example, whether brain cells have their proper number and position,” says Eric Courchesne, a neuroscientist at the University of California, San Diego, who is leading the project. “This could provide a major insight into the cause of autism.”

Autism is a neurodevelopmental disorder characterized by deficits in language and social behavior. While the brains of people with autism appear broadly normal, previous brain-imaging studies have revealed unusual growth patterns in very young children with the disorder. “It’s clear that in the first two years of life, the brain grows too large, too fast,” says Courchesne.

Scientists don’t yet understand the reason for the strange growth spurt–whether it’s caused by too many neurons in a particular part of the brain or a failure to prune extraneous neurons, a common occurrence in normal development. They hope that an unusual set of tools developed for the Allen Brain Atlas, a database of gene expression in the mouse brain, could finally yield clues.

To create the map, researchers at the Allen Institute for Brain Science in Seattle, WA, painstakingly created a comprehensive set of DNA probes that highlight the expression patterns of individual genes. While previous studies have only been able to look at the expression of a handful of genes at a time, these probes can provide a wealth of information by revealing the expression of many genes simultaneously.

Researchers at the Allen Institute have been sifting through the toolbox for probes that can identify different cell types in the human cortex–the most recently evolved part of the brain. The team will use them to study the expression of approximately 25 genes in samples of postmortem brain tissue collected from very young children with autism. “This will give us a much clearer look at how things are disorganized, rather than just saying they are disorganized,” says Ed Lein, director of neuroscience at the Allen Institute.

The researchers will focus on the prefrontal cortex, an area in the frontal lobes involved in higher-order social and emotional communication, and one of the brain regions most affected by abnormal early overgrowth. The DNA probes will allow researchers to compare the location and organization of specific cell types, such as excitatory neurons that connect to brain areas outside of the cortex and inhibitory neurons that form local cortical circuits.

“It’s fundamentally important to identify the cause of that overgrowth,” says Courchesne. “It may help us understand how best to tailor interventions for autism, not just behaviorally, but for medical and chemical interventions down the road.”

The project will be the first to use the tools developed at the Allen Institute to study the neurobiology of human disease. The data will be made publicly available via the Web for other scientists to study, as data from the mouse brain study is now.

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