ASF Grantee Publishes Paper in Nature that Brings Insight to Study of Phelan-McDermid Syndrome and Autism

Published October 16, 2013 in Nature

By Dr. Oleksandr Shcheglovitov

22q13.3 deletion syndrome (also known as Phelan-McDermid syndrome) is a genetic neurodevelopmental disorder characterized by global developmental delay, severely impaired speech, intellectual disability, and autism. The syndrome is caused by the heterozygous microdeletions in the terminal region of chromosome 22. Although, a candidate gene responsible for the neurological abnormalities in patients has been suggested (SHANK3, which encodes a scaffolding protein of excitatory synapses), cellular and molecular defects associated with this syndrome were unknown. In the study published in Nature today, researchers from Stanford University reported that human neurons derived from induced pluripotent stem cells of patients with Phelan-McDermid syndrome and autism have deficits in excitatory synaptic transmission due to reduced number of excitatory synapses. The authors demonstrated that SHANK3 is primarily responsible for these deficits, as neurons from patients had reduced SHANK3 expression and increasing the levels of SHANK3 expression rescued synaptic deficits in patient cells.

The authors also tested several drugs for their ability to increase the number of excitatory synapses in neurons derived from patients and found that prolonged treatment with Insulin Growth Factor 1 (IGF1) completely restores excitatory synaptic transmission in patient cells. Interestingly, IGF1 produced its action by increasing the number of different type of excitatory synapses that express scaffolding protein PSD95 and lack SHANK3 expression.

In summary, this study brings important insights about the cellular and molecular mechanisms involved in the loss and gain of synaptic function in human neurons from patients with Phelan-McDermid syndrome and autism. It also provides encouragement that neurons derived from induced pluripotent stem cells of patients will be useful in understanding and developing treatments for neurodevelopmental and psychiatric disorders.

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