A new analysis of gene expression in the brain suggests that autism blurs the molecular differences that normally distinguish different brain regions. This and other insights provide a new framework for understanding what causes autism and related disorders.
Autism is a complex brain disorder characterized by difficulties with social interactions, poor verbal and nonverbal communication and repetitive behaviors. It’s often grouped with similar disorders that range from mild to severe. These are collectively referred to as autism spectrum disorders (ASD). ASD affects about 1 in 110 American children.
Despite linking a number of genetic factors to ASD, scientists haven’t yet been able to figure out what causes these disorders. A research team led by Dr. Daniel Geschwind of the University of California, Los Angeles, set out to do a broad analysis of gene activity in the brain—a “transcriptomic” analysis—to see what gene expression patterns might reveal about ASD. The study, which was supported by NIH’s National Institute of Mental Health (NIMH) and others, appeared online on May 26, 2011, in Nature.
The team analyzed post-mortem brain tissue samples from people with ASD and healthy controls. They first looked for gene expression abnormalities in brain areas implicated in autism. They found 444 genes that were expressed differently in the cortexes of people with ASD. Genes involved in synapses—the connections between neurons—tended to be under-expressed in people with ASD when compared with healthy brains. Genes involved in immune and inflammatory responses, in contrast, tended to be over-expressed.
The researchers had previously shown that genes tend to turn on and off together in sets or “modules.” An analysis of functional modules revealed differences in expression in 2 modules that correlated highly with autism. One module represents neuron and synapse development. Many of these genes were also implicated in autism in previous, genome-wide studies. The second module is involved in development of other types of brain cells. The researchers believe that these latter gene expression changes are likely not causes of ASD, but rather a result of other factors involved in the disorder.
The scientists also examined differences in gene expression between 2 brain regions—the frontal and temporal (lower middle) cortexes. Among more than 500 genes that are expressed at significantly different levels within the brains of healthy controls, only 8 showed such differences in the brains of people with autism. This suggests that many of the normal molecular distinctions between these regions are missing in autism.
Different mixes of genes normally turn on in different parts of the brain during fetal development to create distinct tissues that perform specialized functions. “Such blurring of normally differentiated brain tissue suggests strikingly less specialization across these brain areas in people with autism,” says Geschwind. “It likely reflects a defect in the pattern of early brain development.”
“This study provides the first evidence of a common signature for the seemingly disparate molecular abnormalities seen in autism,” says NIMH Director Dr. Thomas R. Insel. “It also points to a pathway-based framework for understanding causes of other brain disorders stemming from similar molecular roots, such as schizophrenia and ADHD.”
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