Mutations Causing Syndromic Autism Define an Axis of Synaptic Pathophysiology

Published November 23, 2011 in Nature

New research reveals that two genetic forms of autism, fragile X syndrome and tuberous sclerosis, are actually caused by opposite malfunctions – while fragile X is caused by overproduction of proteins at the synapse, tuberous sclerosis is caused by underproduction. Interestingly, while the causes of fragile X and tuberous sclerosis are distinctly different, both disorders often result in intellectual disability and autism spectrum disorder. Researchers made the discovery while studying mGluR5 (Metabotropic glutamate receptor 5), a receptor on the surface of neurons that is key in aiding communication at the synapse – the junction between neurons. During normal signaling, the mGluR5 receptor binds to the neurotransmitter glutamate after it is released across the synapse, resulting in the production of new synaptic proteins. Fragile X protein (FMRP) halts protein synthesis to ensure that the appropriate amount is produced — in fragile X syndrome, changes to the gene that controls FMRP allow synaptic proteins to continue production unchecked, resulting in too much protein. Researchers have previously shown that introducing a substance to block mGluR5 reverses some of the symptoms of fragile X, and human drug trials are currently underway. Armed with an understanding of the underlying causes of fragile X, researchers in this study examined mice with tuberous sclerosis mutations and discovered something surprising. In this case, the disorder was caused by the opposite malfunction – too little protein synthesis at the synapse, which could be treated with a drug stimulating mGluR5. Further, when the researchers bred the two mice together, many of their autistic features went away. The findings of the study indicate that proper brain function can only occur within a narrow range of mGluR5 protein synthesis – changes in either direction lead to syndromes with similar behavioral symptoms. This also suggests that drug treatments for autism spectrum disorder will need to be individually tailored, as conditions that appear similar may have quite different underlying causes.

–IACC 2011 Summary of Advances in ASD Research

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