01:49pm Thursday 17 October 2019

Children's National Researchers Unlock a Key Cause of Fragile X Syndrome

Washington, DC — Researchers with the Center for Neuroscience Research at Children’s National Medical Center have identified a brain defect responsible for many of the social and emotional problems associated with Fragile X Syndrome (FXS). Specifically, the investigators uncovered that neuronal inhibitory neurotransmission, a major form of communication in the brain, is significantly diminished in the animal model of FXS. FXS is the most common inherited cause of mental retardation and the leading known genetic cause of autism as one-third of people with FXS also have autism spectrum disorders.

In addition to this discovery, in slice cultures the team also demonstrated the effectiveness of a drug that may correct the defect, which may inform the development of therapies for FXS and other autism spectrum disorders. The next step is to collaborate with clinical researchers to test the drug more broadly for safety and efficacy. According to Children’s National researchers and other studies, the national and international neuroscience research community is exploring how best to take that next step.

The discoveries resulted from the three-year collaboration of two laboratories at Children’s National and a Kennedy Krieger-Johns Hopkins laboratory. One laboratory, led by Joshua Corbin, PhD, co-principal investigator, works to understand the basic mechanisms of development of the amygdale—a specific part of the brain intimately involved in behavioral deficits in autism spectrum disorders. The other laboratory, led by Molly Huntsman, PhD, co-principal investigator, studies how neurotransmitters that are responsible for inhibitory and excitatory behavior work for proper communication in the brain.

A paper detailing the research was published in the July issue of the Journal of Neuroscience.

“Our two groups pooled our expertise to explore our hypothesis that there is something deficient in the development of the amygdala that leads to the abnormal behavioral manifestations that are seen in Fragile X, and more broadly in autism,” said Dr. Corbin.

“Circuits in a typical brain run like a well-oiled engine—everything is happening and firing at the right time and in the right place,” said Dr. Huntsman. “That is because excitatory neurotransmitters and inhibitory neurotransmitters keep everything balanced and in-tune. An imbalance in those neurotransmitters can result in brain dysfunction.”

Researchers found that in the Fragile X model, neurons do not communicate with each other properly. There is too little of the specific neurotransmitter GABA (γ-aminobutyric acid), which is the neurotransmitter required for inhibition. This made the system hyper-excitable. After identifying this deficit, the team looked for ways to make the GABA receptors more sensitive. They experimented with a drug called THIP, a GABA-specific, GABA receptor subtype agonist, and found that it restored the balance in neuronal communications.

“In our slice preparation, the drug actually was able to correct back to normal—not over-correcting or too under-correcting,” said Dr. Huntsman. “This discovery could be significant to the development of therapies specifically for Fragile X and perhaps for other autism spectrum disorders.”

“The more we understand the mechanism of the deficit, the more deeply we can think about how to fix it,” continued Dr. Corbin. “Neurological disorders are complex, so no one can take a single approach. One of the advantages of the model at Children’s National is that we are able to work together across multiple teams and in partnership with our clinical colleagues to tangibly solve neurological disorders in children.”

Others authors of the study included Jose Luis Olmos-Serrano of the Center for Neuroscience Research; Scott M. Paluszkiewicz and Brandon S. Martin, of the Center for Neuroscience Research and the Interdisciplinary Program in Neuroscience at the Georgetown University School of Medicine; and Walter E. Kaufmann, MD, of the Center for Genetic Disorders of Cognition and Behavior at the Kennedy Krieger Institute, Johns Hopkins University School of Medicine.

Contact: Paula Darte or Jennifer Leischer Stinebiser: 202-476-4500

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Children’s National Medical Center in Washington, DC, has been serving the nation’s children since 1870. Home to Children’s Research Institute and the Sheikh Zayed Institute for Pediatric Surgical Innovation, Children’s National is consistently ranked among the top pediatric hospitals by U.S.News & World Report and the Leapfrog Group. With 283 beds, more than 1,330 nurses, 550 physicians, and seven regional outpatient centers, Children’s National is the only exclusive provider of pediatric care in the Washington metropolitan area. Children’s National has been recognized by the American Nurses Credentialing Center as a Magnet® designated hospital, the highest level of recognition for nursing excellence that a medical center can achieve.

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