New mouse model for Phelan-McDermid Syndrome

A team of researchers, led by Joseph Buxbaum, PhD, Director of the Seaver Autism Center for Research and Treatment at Mount Sinai School of Medicine, created and studied a mouse model that has a loss of one copy of the SHANK3 gene. The team discovered that nerve cells communicate less effectively when one copy of the SHANK3 gene is missing. In addition, missing a copy of this gene hinders normal nerve-cell learning processes. This finding could explain how the loss of a copy of  SHANK3 contributes to the behavioral manifestations of Phelan-McDermid Syndrome. Dr. Buxbaum  said, “Armed with this breakthrough, we are beginning to test drugs in these mice that are aimed at treating the syndrome at its root cause by improving nerve cell communication.”

The team included lead authors Ozlem Bozdagi, MD, PhD, and Takeshi Sakurai, MD, PhD, as well as senior authors Patrick Hof, MD, Qiang Zhou, PhD, and Jacqueline Crawley, PhD.

Dr. Buxbaum explains, “We know that the SHANK3 mutation plays a central, causative role in Phelan-McDermid Syndrome, but we wanted to learn more about how it does this.” Mice were genetically engineered to lack one copy of SHANK3 – comparable to patients who have a SHANK3 deletion or mutation on one copy of the gene. The team analyzed both nerve cell activity, and examined social behaviors in the mice.

The researchers identified impaired nerve cell communication in the SHANK3-deficient group, and noted that the nerve cells and synapses experienced altered functional and structural plasticity. The site at the National Institute of Mental Health, Laboratory of Behavioral Neuroscience, led by Dr. Crawley observed a decreased level of social interaction between male and female SHANK3 mutant mice.

“These results have helped us identify a pathological mechanism behind the neurobehavioral manifestations of Phelan-McDermid Syndrome,” said Dr. Buxbaum. “We hope and expect that, like other developmental disorders such as Fragile X syndrome, the use of mouse models will lead directly to clinical trials in Phelan-McDermid Syndrome that can benefit patients.”

A report of this study is available for free through the open-access journal Molecular Autism at the following link:

This study was sponsored by the Seaver Foundation, and a special multi-investigator grant given to co-authors Drs. Buxbaum, Crawley, Hof and Zhou from the Simons Foundation. In addition, the study was supported by a generous gift from Paulina Rychenkova, PhD, and William Gibson.

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