How Environmental Factors May Contribute To Autism

A family of proteins controlling the activity of a broad set of neuronal genes could be the root of autism spectrum disorder.

The symptoms of autism spectrum disorder could arise from inhibition of a broad set of genes involved in neuronal development, according to a study published in the Journal of Experimental Medicine (1). Inhibiting gene-regulating proteins called bromodomain and extraterminal domain–containing proteins (BETs) led to suppression of hundreds of neuronal genes, followed by the development of an autism-like syndrome in young mice. The findings support the view that environmental factors trigger epigenetic changes to contribute to the development of autism spectrum disorder.

“This study is, to our knowledge, the first model of autism induced by a pharmacological compound,” said first author Josefa Sullivan of the Icahn School of Medicine at Mount Sinai. “It could be used as a new and easy way to study autism-like behaviors in mice and to test the effects of novel drugs.”

Autism spectrum disorder has been associated with numerous gene mutations. But a large number of autism-related genes encode proteins that regulate the activity of a set of genes. This observation motivated Sullivan and senior study author Anne Schaefer to examine whether epigenetic factors contribute to the development of the disorder.

To test this idea, Sullivan’s team developed a novel, highly specific, brain-permeable inhibitor of BET proteins. This family of proteins regulates the activity of genes by binding to and affecting the structure of chromatin.

In the new study, the researchers found that BET inhibition suppressed hundreds of neuronal genes, many of which were previously implicated in autism-spectrum disorder. Several of these genes are also known to regulate neuronal development and signal transmission between neurons. Moreover, mice treated with the BET inhibitor showed autism-like behaviors, such as heightened anxiety and social deficits.

“Our findings suggest that environmental factors or toxins that affect general gene transcription during brain development may contribute to autism spectrum disorder, which would have broad implications in public health,” Sullivan said.

References

1. Sullivan JM et al. Autism-like syndrome is induced by pharmacological suppression of BET proteins in young mice. J Exp Med. 2015 Oct 19;212(11):1771-81. doi: 10.1084/jem.20151271. Epub 2015 Sep 21.

2. Dawson MA. Regulating BETs at central station. J Exp Med. 2015 Oct 19;212(11):1754. doi: 10.1084/jem.21211insight1.