Autistic children tend to be introverted, choosing to play by themselves rather than with others. These behaviours are also visible in mice, who can also prefer to interact with an inanimate object over another mouse. These analogous behaviours were examined in a U of T study led by graduate student Mathieu Quesnel-Vallieres. The team’s findings, which were recently published in Molecular Cell, offer new insights on the enigmatic biology of autism spectrum disorder (ASD).

ASD is a neurological disorder that impacts 1 in 68 children. It is particularly difficult to study “because molecular pathways involved in the pathogenesis of autistic disorders diverge between specific cases,” explained Quesnel-Vallieres.

Fortunately, Quesnel-Vallieres and his team in the research labs led by Dr. Ben Blencowe and Dr. Sabine Cordes, professors in U of T’s Department of Molecular Genetics, have overcome this hurdle. They discovered a causal link between the nSR100 protein and mice that appear to have autism.

When the researchers reduced the levels of nSR100 protein by half the mice appeared normal and healthy. It was not until the mice underwent a series of behavioral tests assessing sociability that a change became evident.

The mice with reduced nSR100 consistently scored high on measures attributed to “antisocial” behaviour and showed a heightened sensitivity to auditory stimulation — similar to the sensory hypersensitivity experienced by humans with autism. These effects were also more dominant in male mice, again paralleling human autism presentation.

To recognize the relationship between nSR100 and autism, the researchers first needed to understand the protein’s normal function in the body; it is a master regulator of a process called alternative splicing, whereby multiple proteins are made out of the same genetic sequence to create a greater diversity of proteins.

Alternative splicing is particularly important in the development and functioning of the nervous system. “Neurons use this mechanism more than any other cell because they are more complex and require a vast repertoire of proteins to establish countless connections with other neurons and organize brain circuits,” explained Quesnel-Vallieres.

nSR100 therefore plays a critical role in the overall proper functioning of the nervous system. “Our work shows that changing alternative splicing even subtly can lead to the often nuanced differences in social behavior and nervous system function that accompany autism spectrum disorder,” said Cordes.

Blencowe was initially responsible for research into the nSR100 protein. His lab had previously illustrated that in a large cohort of human autistic brain samples, where the cause of autism was unknown, one-third of patients had disrupted alternative splicing and decreased levels of nSR100.

This gave Quesnel-Vallieres the idea to deplete nSR100 levels in mice to those found in ASD patients. In addition to the autistic-like behaviour described previously, the mice also had altered neuronal network communication and structure.

Quesnel-Vallieres and his team then aimed to understand how nSR100 levels initially became diminished in humans. Strikingly, they found that when mouse neurons were depolarized in a dish to stimulate neuronal activity, there was an accompanied decrease in nSR100 levels. These results suggest that changes in neuron excitability during development can affect nSR100 levels in the brain, and could be the cause of a substantial proportion of autism cases.

Dr. Karun Singh, assistant professor at the Stem Cell and Cancer Research Institute of McMaster University, also commented that nSR100 may in fact control the expression of many other autism risk genes and could act as a central signaling hub that is aberrant in ASD.

Blencowe explained that his lab is “currently exploring tangible ways to determine which group of autistic patients have reduced levels of nSR100. Ultimately, our goal is to determine whether drugs that restore normal levels of nSR100 can represent a viable treatment option for autistic patients.”

With files from Aditya Chawla

Editor’s note: A previous version of this article incorrectly stated that human neurons were depolarized in a dish as part of an experiment. In fact, mouse neurons were used. 

Like our content? Subscribe to our weekly newsletter

* indicates required