Brain responses to language in young children with autism linked to modified gene expression

The results were published online November 26 in the journal Nature Neuroscience.

The large-scale gene-brain association occurs differently in infants diagnosed with Autism Spectrum Disorder (ASD) and whose language development is poor compared to young children have an ASD and who develop language well or develop generally. This large-scale association involved a very large number of genes, many of which are commonly expressed in many tissues, including the brain and leukocytes, a type of blood cell.

"Many other genes involved in prenatal brain development are known to be human, are related to vocal learning and, importantly, have been directly involved in ASD by others." genetic studies and post mortem, "said the first author, Michael. Lombardo, Ph.D., assistant professor of psychology at the University of Cyprus. "The results show that different molecular biological mechanisms underlie functional brain development in an ASD subtype with poor linguistic outcomes, and this biology is present before such results are known."

As a result, say the authors, the work suggests that functional neuroimaging measurements and gene expression levels in white blood cells could offer a new in vivo way to identify the relevant molecular mechanisms for the brain in ASD.

"They also show that the use of peripheral blood samples could help us better understand how brain development evolves dynamically over the course of life," said Eric Courchesne, co-author, Ph.D. .D., Professor of Neuroscience at the UC San Diego School of Medicine. "For example, the methodology behind this work may be used in the future to monitor how a patient's biology, at the level of molecular and neuronal systems, responds to treatment or changes occurring during the course of time. of life, according to different results. "

Early language development in autism is highly variable, noted the authors. "Some infants with autism are very little verbal, while at the other extreme, many people develop language similar to that of developing children," Lombardo said. "An important and long-standing question is whether these very different linguistic profiles in autism are distinctions of subtypes that indicate different biological bases."

"We need to better understand the biological underpinnings of different early languages ​​in the development of autism, as early language ability is one of the most important predictors of early reaction and subsequent outcomes," he said. declared Courchesne. "If we can understand this biology, it could have a significant impact on future work to determine how to make the most of the changes in biology that can significantly improve long-term outcomes for patients."

At the University of San Diego School of Medicine, a research team led by Courchesne and co-lead author Karen Pierce, Ph.D., professor of neuroscience and co-director with Courchesne's Center of Excellence for Autism from the University of San Diego, collected blood samples 118 infants, aged on average 29 months or a little under 2 and a half years, measured the transcriptional activity of all the genes coding for the proteins of the genome.

The UC San Diego team also collected fMRI data during natural sleep in infants exposed passively to speech stimuli. Using the behavioral clinical assessment data collected each year repeatedly between one and four years, Pierce divided autistic infants into subtypes with low or satisfactory language scores at age three to four. .

Lombardo then used advanced biostatistical analyzes to group genes into highly correlated "gene modules", evaluating the relationship between module activity and the neural response of the entire brain to speech. The researchers found that module activity related to neuronal responses to speech was widespread throughout the genome, encompassing several thousand genes working in a coordinated manner.

The discovery, said the authors, was strongly linked to in vivo The fMRI response in living patients is a methodological advance that may help improve the way clinicians determine which people will respond to different types of treatment.

"One of the biggest challenges in advancing the understanding of ASD has been the lack of a method for identifying differences in gene activity underlying the initial brain differences and clinical symptoms seen in patients." young children with ASD, "said Courchesne. "It's because the living toddler's brain is inaccessible to the direct measurement of gene activity. As such, the differences in gene activity underlying brain dysfunction and to emerging clinical symptoms remained completely unknown – until now.

"Our method takes advantage of the fact that a large number of genes and gene networks relevant to ASD and brain and prenatal expression largely express themselves in readily accessible non-brain tissues, such as leukocytes, as well as that in the brain, the activity of genes, it is possible to advance the understanding of this key biology in live toddlers with ASD.This unique method can not only have a considerable impact on the understanding of the molecular basis of TSA, but also on how to monitor changes in the biology based on early effects.We believe that this method can link the molecular mechanisms of available peripheral samples, such as blood, with in vivo brain measurements using neuroimaging helps us considerably. "

Courchesne said the researchers plan to expand their work into clinically relevant directions, such as tracking the response to treatment of subtypes of ASD and potentially leveraging information from the community. Gene expression, fMRI, and clinical measures to develop early tools to predict the language outcomes of young children. age.

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More information:
Michael V. Lombardo et al. Large-scale associations between leukocyte transcriptome and BOLD responses to speech differ among sub-types of early language outcomes of autism, Nature Neuroscience (2018). DOI: 10.1038 / s41593-018-0281-3