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Jun 3, 2011

Autism Found to Blur Distinctions Between Brain Regions

Autism Found to Blur Distinctions Between Brain Regions

Researchers looked at the cortex of postmortem brains.[V. Yakobchuk/Fotolia.com]

  • Autism blurs the molecular differences that normally distinguish different brain regions, a new study suggests. Among more than 500 genes that are normally expressed at significantly different levels in the front versus the lower middle part of the brain's cortex, only eight showed such differences in brains of people with autism, the researchers say. 

    "Such blurring of normally differentiated brain tissue suggests strikingly less specialization across these brain areas in people with autism," explains Daniel Geschwind, M.D., Ph.D., of the University of California, Los Angeles. "It likely reflects a defect in the pattern of early brain development."

    Dr. Geschwind and colleagues published their study online May 26 in Nature. The paper is titled “Transcriptomic analysis of autistic brain reveals convergent molecular pathology.” The research was based on postmortem comparisons of brains of people with the disorder and healthy controls.

    In an earlier study the researchers showed that genes that turn on and off together at the same time hold clues to the brain's molecular instructions. These pathways of co-expressed genes can reveal genetic co-conspirators in human illness, through what Dr. Geschwind and colleagues call "guilt by association." A gene is suspect if its expression waxes and wanes in sync with others in an illness-linked pathway.

    Using this strategy, the researchers first looked for gene-expression abnormalities in brain areas implicated in autism. They found 444 such differently expressed genes in the cortexes of postmortem brains of autistic people.

    Most of the same genes turned out to be abnormally expressed in the frontal cortex as in the temporal cortex (lower middle) of autistic brains. Of these, genes involved in synapses tended to be underexpressed when compared with healthy brains. Genes involved in immune and inflammatory responses tended to be overexpressed. These were determined not to be genetic causes of the illness but likely gene-expression changes related to secondary inflammatory, immune, or possible environmental factors involved in autism. 

    Autistic and healthy control brains were similarly organized—modules of co-expressed genes correlated with specific cell types and biological functions. Yet normal differences in gene-expression levels between the frontal and temporal cortex were missing in the pathways of autistic brains.

    This suggests that the normal molecular distinctions between these regions are nearly erased in autism, likely affecting how the brain works. Strikingly, among 174 genes expressed at different levels between the two regions in two healthy control brains, none were expressed at different levels in brains of people with autism.

    Among genes in brain pathways involved in neuron and synapse development that were underexpressed in autism, many were reportedly implicated in autism in previous, genome-wide studies. So, several different lines of evidence now converge, pointing to genes in this M12 module as genetic causes of autism, the scientists state. 

    This newfound ability to see genes in the context of their positions in these pathways provides hints about how they might work to produce illness, according to Dr. Geschwind and colleagues. For example, from its prominent position in the M12 module, the researchers traced a potential role in creating defective synapses to a gene previously implicated in autism.

    Follow-up studies should explore whether the observed abnormalities in the patterning of gene expression might also extend to other parts of the brain in autism, say the researchers.


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