Scripps Florida Scientists Move Closer to a Personalized Treatment Solution for Intellectual Disability

Scripps Florida Scientists Move Closer to a Personalized Treatment Solution for Intellectual Disability JUPITER, FL January 21, 2015 Scientists from the Florida campus of The Scripps Research Institute (TSRI) have produced an approach that protects animal models against a type of genetic disruption that causes intellectual disability, including serious memory impairments and altered anxiety levels.

The findings, which focus on treating the effects of mutations to a gene known as Syngap1, have been published online ahead of print by the journal Biological Psychiatry.

Our hope is that these studies will eventually lead to a therapy specifically designed for patients with psychiatric disorders caused by damaging Syngap1 mutations, said Gavin Rumbaugh, a TSRI associate professor who led the study. Our model shows that the early developmental period is the critical time to treat this type of genetic disorder.

Damaging mutations in Syngap1 that reduce the number of functional proteins are one of the most common causes of sporadic intellectual disability and are associated with schizophrenia and autism spectrum disorder. Early estimates suggest that these non-inherited genetic mutations account for two to eight percent of these intellectual disability cases. Sporadic intellectual disability affects approximately one percent of the worldwide population, suggesting that tens of thousands of individuals with intellectual disability may carry damaging Syngap1 mutations without knowing it.

In the new study, the researchers examined the effect of damaging Syngap1 mutations during development and found that the mutations disrupt a critical period of neuronal growth a period between the first and third postnatal weeks in mouse models. We found that a certain type of cortical neuron grows too quickly in early development, which then leads to the premature formation of certain types of neural circuits, said Research Associate Massimilano Aceti, first author of the study.

The researchers reasoned that this process might cause permanent errors in brain connectivity and that they might be able to head off these effects by enhancing the Syngap1 protein in the newborn mutant mice. Indeed, they found that a subset of neurons were misconnected in the adult mutant mice, suggesting that early growth of neurons can lead to life-long neural circuit connectivity problems. Then, using advanced genetic techniques to raise Syngap1 protein levels in newborn mutant mice, the researchers found this strategy completely protected the mice only when the approach was started before this critical developmental window opened.

As a result of these studies, Rumbaugh and his colleagues are now developing a drug-screening program to look for drug-like compounds that could restore levels of Syngap1 protein in defective neurons. They hope that, as personalized medicine advances, such a therapy could ultimately be tailored to patients based on their genotype.

In addition to Rumbaugh and Aceti, other authors of the study, Syngap1 Haploinsufficiency Damages a Postnatal Critical Period of Pyramidal Cell Structural Maturation Linked to Cortical Circuit Assembly, include Thomas K. Creson, Thomas Vaissiere, Camilo Rojas, Wen-Chin Huang, Ya-Xian Wang, Ronald S. Petralia, Damon T. Page and Courtney A. Miller of TSRI. For more information, see http://www.biologicalpsychiatryjournal.com/article/S0006-3223%2814%2900593-9/abstract

This work was supported by the National Institutes of Health's National Institute for Neurological Disorders and Stroke (R01NS064079), National Institute for Mental Health (R01MH096847), National Institute for Drug Abuse (R01 DA034116; R03 DA033499) and National Institute on Deafness and Other Communication Disorders/National Institutes of Health Intramural Research Program; Mrs. Nancy Lurie; and the State of Florida.

About The Scripps Research Institute

The Scripps Research Institute (TSRI) is one of the worlds largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs about 2,700 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists including two Nobel laureates work toward their next discoveries. The institutes graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.

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