Gene Expression in the Brain Offers Clues to Autism’s Roots

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Increasingly, scientists are studying the brain in people with autism, seeking a molecular signature that might help identify the complex disorder as it develops or some structural clue to its causes. Now an intriguing new study on patterns of gene expression in the autistic brain offers fresh insight.

Led by Dr. Dan Geschwind, director of the Center for Autism Research and Treatment at the University of California, Los Angeles (UCLA), researchers measured levels of gene expression — which determines the synthesis of various of proteins, each with a specific task in the cell — in the brain tissue of 19 autistic people and 17 healthy ones. The scientists report Wednesday in Nature that they have discovered certain patterns of expression common to the autistic brain.

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Working with the brain tissue of youngsters after their death, Geschwind and his team found that compared with nonautistic children, those who had the disorder showed a marked drop in gene expression in two areas of the cerebral cortex, where higher-order processing occurs — the frontal lobe, which plays a role in judgment, creativity, emotion and speech, and the temporal lobe, which is involved in hearing, language and the processing of sounds. These areas have been implicated in autism before.

In addition, Geschwind found that healthy brains showed distinct differences in the level of expression of some 500 genes between the frontal and temporal lobes. But this difference in expression was missing in the autistic brains; the features that would normally distinguish the two regions had disappeared, Geschwind said.

“To see strong signals [that autistic children have] in common tells us there is a lot more hope for the field in some ways and that even though there may be many different causes of autism, there are some shared underlying molecular features. That to me was a big change in the way many of us think about autism,” he says.

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The fact that the autistic brains showed lower levels of gene expression in the frontal and temporal lobes makes sense, experts said. “We know that differences in gene expression patterns are what define the development of the nervous system,” says Robert Ring, vice president for translational research at Autism Speaks. “So I’m not surprised that this paper teaches us that a specific network of genes helps to explain some of the dysregulation in that pattern in autism. The results give us tangible evidence on which we can further expand our research efforts.”

Pinpointing these shared genetic pathways means that it might be possible to develop more targeted and effective therapies to address some of the behavioral symptoms of autism, which include deficiencies in language and processing of emotion, and socially inappropriate behavior.

Two other patterns of gene expression also emerged from Geschwind’s research: first, the autistic brains tended to show less expression of genes involved in neuron function and communication; further, they showed higher levels of expression of genes related to immune function and inflammation. Several of the genes involved, Geschwind said, had been previously linked to autism.

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Once Geschwind’s group identified the distinct patterns of gene expression in autistic and normal brains, they compared them with gene expression patterns that occur during normal fetal development. The idea was to start answering the question of how early developmental deficits may begin in autism.

It turns out that even in the womb, the fetal brain begins to show differences in gene expression between the frontal and temporal lobes, suggesting that the developmental abnormality associated with autism may develop then too.

That’s important, because autism is usually not diagnosed with any certainty until infants are about two years old and have begun showing outward deficits in language and social behaviors. “If we had the ability to study these networks of gene activity in brains of living patients, we could easily lay the foundation of a completely novel approach to diagnosis or measurement of treatment outcomes,” says Ring. “That would be huge.”

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Applying the current findings to living people will be the next step for autism researchers. It’s not clear yet how relevant the brain tissue results may be for diagnosing or treating children. But given that the developmental differences appear to begin early on, Geschwind is hopeful that researchers will eventually identify certain proteins or other markers of gene expression that may be detectable in the blood help signal autism.

Geschwind notes that his group focused on gene expression in just two regions of the brain, and that other shared aberrations may emerge when experts delve into other parts of the brain. “Now we have this incredible overlap among autistic brains, which is nice,” he says. “It’s interesting, but it’s just a start.”