Mount Sinai Researchers Generate First In-Depth Characterization of a Genetically Modified Rat Model for Autism and Intellectual Disability
Researchers at The Seaver Autism Center for Research and Treatment at Mount Sinai have generated and characterized a genetically modified rat model of autism and intellectual disability, according to a study conducted at the Icahn School of Medicine at Mount Sinai and published January 31 in the journal eLife. Researchers report that in this novel rat model, the hormone oxytocin significantly improved social memory, attention, and nerve cell activity.
The Mount Sinai study focused specifically on the production and characterization of a first genetically modified rat model for Phelan-McDermid syndrome, a developmental disorder with high rates of autism, intellectual disability, attention deficits, and severe language delay. One or more of these symptoms is found in up to 10 percent of children, with limited medicines available for treatment. Phelan-McDermid syndrome is caused by a mutation in a gene called Shank3, leading to a malfunction of nerve cells, especially at the region known as the synapse, where nerve cells communicate with each other.
“Our rat model provides the research community with a valuable tool to study how altered function of synapses and nerve cells leads to subsequent deficits in behavior and cognition that are associated with multiple developmental disorders, including Phelan-McDermid syndrome.” says Hala Harony-Nicolas, PhD, an instructor at The Seaver Autism Center, and the lead scientist on this study. “Such studies require sophisticated approaches that are significantly more challenging in other model systems as compared to rats, underscoring the value of this model.”
The new model, referred to as the Shank3-deficient rat, mimics a human Shank3 mutation and exhibits deficits in a form of social behavior that depends on long-term memory, attention, and communication between nerve cells. The research team discovered that behavioral and synaptic deficits could be improved by treatment with the pro-social hormone oxytocin, which is known to be a powerful modulator of mammalian social behavior. Oxytocin was also able to reverse attention deficits that were not related to any social context, a finding that has not been seen in previous studies.
These findings provide important leads into how Shank3 plays a role in synapse development and function and, ultimately, behavior. In addition, the effect of oxytocin on reversing developmental deficits provides a tool to understand the causes of nerve cell and behavioral deficits and to develop novel treatments.
“One of the most surprising and promising findings of this study is the effect oxytocin had on attention deficits beyond its known effects on social memory,” says Joseph D. Buxbaum, PhD, senior author of the publication and Director of The Seaver Autism Center. “This study is important for understanding developmental disorders broadly and is also the first to indicate that individuals with Phelan-McDermid syndrome may particularly benefit from oxytocin treatment, a hypothesis that is being further examined in ongoing clinical studies at the Seaver Autism Center.”
The study was funded by the Beatrice and Samuel A. Seaver Foundation, the National Institute of Mental Health, the Human Frontier Science Program, the Israel Science Foundation, Autism Speaks, and by a generous gift from William G. Gibson and Paulina Rychenkova, PhD.
About the Seaver Autism Center for Research and Treatment at Mount Sinai
The Seaver Autism Center for Research and Treatment at Mount Sinai conducts progressive research studies aimed at understanding the multiple causes of autism spectrum disorder (ASD). The multidisciplinary team is composed of experts in the fields of genetics, molecular biology, model systems, neuroimaging, biomarkers, diagnosis, and experimental therapeutics who are dedicated to discovering the biological causes of ASD. The Center strives to develop innovative diagnostics and treatments for integration into the provision of personalized, comprehensive assessment and care for people with ASD. The Seaver Autism Center was founded through the generous support of the Beatrice and Samuel A. Seaver Foundation. For more information, visit www.seaverautismcenter.org.
About the Mount Sinai Health System
The Mount Sinai Health System is New York City's largest academic medical system, encompassing eight hospitals, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. Mount Sinai advances medicine and health through unrivaled education and translational research and discovery to deliver care that is the safest, highest-quality, most accessible and equitable, and the best value of any health system in the nation. The Health System includes approximately 7,300 primary and specialty care physicians; 13 joint-venture ambulatory surgery centers; more than 415 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and more than 30 affiliated community health centers. The Mount Sinai Hospital is ranked on U.S. News & World Report's "Honor Roll" of the top 20 U.S. hospitals and is top in the nation by specialty: No. 1 in Geriatrics and top 20 in Cardiology/Heart Surgery, Diabetes/Endocrinology, Gastroenterology/GI Surgery, Neurology/Neurosurgery, Orthopedics, Pulmonology/Lung Surgery, Rehabilitation, and Urology. New York Eye and Ear Infirmary of Mount Sinai is ranked No. 12 in Ophthalmology. Mount Sinai Kravis Children's Hospital is ranked in U.S. News & World Report’s “Best Children’s Hospitals” among the country’s best in four out of 10 pediatric specialties. The Icahn School of Medicine is one of three medical schools that have earned distinction by multiple indicators: ranked in the top 20 by U.S. News & World Report's "Best Medical Schools," aligned with a U.S. News & World Report "Honor Roll" Hospital, and No. 14 in the nation for National Institutes of Health funding. Newsweek’s “The World’s Best Smart Hospitals” ranks The Mount Sinai Hospital as No. 1 in New York and in the top five globally, and Mount Sinai Morningside in the top 20 globally.