Brain activity of microRNAs gives clues about autism
Small regulatory RNA molecules are most active between infancy and early childhood in a region of the brain known for complex thinking and behavior, reports a new study published 6 August in Molecular Psychiatry1. The finding, based on an analysis of postmortem brains, may provide insight into what goes wrong in neurodevelopmental disorders such as autism.
These RNA fragments, called microRNAs (miRNAs), can affect protein production. There is some evidence that miRNAs are expressed differently in people with autism than in controls, suggesting they play a role in the disorder.
The study is the first analysis of miRNA activity during normal human brain development. The researchers used elevated expression of a miRNA as a proxy for its activity. By studying normal miRNA activity, researchers can learn where and when it goes awry in the brains of people with autism.
"Understanding those developmental patterns potentially could let you identify regulatory pathways that can have altered function during development and give rise to certain diseases," says lead investigator Owen Rennert, head of clinical and developmental genomics at the National Institute of Child Health and Human Development in Bethesda, Maryland.
There are about 900 miRNAs identified in the human brain. The researchers found that only 75 of them become more active going from infancy into adolescence. That’s surprising, given the dramatic developmental changes that occur in this time frame, says Schahram Akbarian, professor of psychiatry and neuroscience at Mount Sinai School of Medicine in New York, who was not involved in the study.
"I am amazed how few molecules change their expression within each brain region," Akbarian says. "It looks like many of the psychological and cognitive changes during normal human development cannot be fully captured in molecular assays from postmortem brains."
In the study, researchers analyzed miRNA expression in 18 postmortem brains from individuals who were between 4 months and 19 years of age. They acquired the miRNA data from an analysis of postmortem brains by the Allen Institute for Brain Science.
The researchers focused on tissues from the prefrontal cortex, hippocampus and cerebellum — areas linked to autism and to higher cognitive skills such as planning and problem-solving.
In each tissue sample, the researchers looked for miRNA expression to determine where the miRNAs are most active in the brain.
The dorsolateral prefrontal cortex — an area associated with personality, long-term planning and complex cognitive functions — shows the most miRNA activity, with 35 miRNAs expressed at high levels from infancy to adolescence. The cerebellum shows elevated expression of 22 miRNAs, and the hippocampus and other regions of the prefrontal cortex have a dozen or fewer.
"The fact that the [dorsolateral prefrontal cortex] shows the most change during normal development makes a lot of sense, because there is higher functioning in this brain region," Akbarian says.
The researchers also nailed down the period of greatest activity as the interval between infancy and early childhood — 4 months to 4 years of age — rather than from early to later childhood or adolescence. The brain is known to undergo dramatic molecular changes during early childhood2.
The results suggest that interventions for autism may work if they're given early enough, Akbarian says.
Genes associated with neurological disorders that emerge during childhood or early adulthood, including autism, bipolar disorder and schizophrenia, have more interactions with miRNAs than those implicated in neurodegenerative disorders such as Parkinson's, Alzheimer's and Huntington's diseases, the study shows.
The researchers also found a subset of 40 miRNAs that are more active in girls than in boys, especially during adolescence. This is intriguing, because autism is more prevalent in males.
However, experts not involved in the study say the number of postmortem brains is too small to find any sex differences. A 2012 study of 269 postmortem brains did not find miRNA differences between boys and girls in the prefrontal cortex3. Experts also caution that the researchers’ information about the miRNA expression came from a database, rather than from their own analysis of brain tissue.
"I think their finding is intriguing, but it's quite preliminary," says Peng Jin, professor of human genetics at Emory University School of Medicine in Atlanta, Georgia, who was not involved in the study.
Rennert acknowledges the study is limited, but says it may inspire others to dig deeper into miRNA expression during development.
"We want to stimulate other people who have different approaches, different methods or different material available to assess whether these predicted consequences are indeed true biologic consequences," he says.
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1: Ziats M.N. and O.M. Rennert Mol. Psychiatry Epub ahead of print (2013) PubMed
2: Shulha H.P. et al. PLoS Genet. 9, e1003433 (2013) PubMed
3: Colantuoni C. et al. Nature 478, 519-523 (2011) PubMed