A team of researchers from SUNY Downstate Medical Center (SUNY Downstate) and Sanford-Burnham Medical Research Institute (Sanford-Burnham) has found that deficiencies in hyaluronan, also known as hyaluronic acid or HA, can lead to spontaneous epileptic seizures. HA is a polysaccharide molecule widely distributed throughout connective, epithelial, and neural tissues, including the brain's extracellular space (ECS). Their findings, published on April 30 in The Journal of Neuroscience, equip scientists with key information that may lead to new therapeutic approaches to epilepsy.
The multicenter study used mice to provide the first evidence of a physiological role for HA in the maintenance of brain ECS volume. It also suggests a potential role in human epilepsy for HA and genes that are involved in hyaluronan synthesis and degradation.
While epilepsy is one of the most common neurological disorders—affecting approximately one percent of the population worldwide—it is one of the least understood. It is characterized by recurrent spontaneous seizures caused by the abnormal firing of neurons. Although epilepsy treatment is available and effective for about 70 percent of cases, a substantial number of patients could benefit from a new therapeutic approach.
"Hyaluronan is widely known as a key structural component of cartilage and important for maintaining healthy cartilage. Curiously, it has been recognized that the adult brain also contains a lot of hyaluronan, but little is known about what hyaluronan does in the brain," said Yu Yamaguchi, MD, PhD, professor in the Human Genetics Program at Sanford-Burnham.
"This is the first study that demonstrates the important role of this unique molecule for normal functioning of the brain, and that its deficiency may be a cause of epileptic disorders. A better understanding of how hyaluronan regulates brain function could lead to new treatment approaches for epilepsy," Yamaguchi added.
The extracellular matrix of the brain has a unique molecular composition. Earlier studies focused on the role of matrix molecules in cell adhesion and axon pathfinding during neural development. In recent years, increasing attention has been focused on the roles of these molecules in the regulation of physiological functions in the adult brain.
In this study, the investigators examined the role of HA using mutant mice deficient in each of the three hyaluronan synthase genes (Has1, Has2, Has3).
"We showed that Has-mutant mice develop spontaneous epileptic seizures, indicating that HA is functionally involved in the regulation of neuronal excitability. Our study revealed that deficiency of HA results in a reduction in the volume of the brain's ECS, leading to spontaneous epileptiform activity in hippocampal CA1 pyramidal neurons," said Sabina Hrabetova, MD, PhD, associate professor in the Department of Cell Biology at SUNY Downstate.
"We believe that this study not only addresses one of the longstanding questions concerning the in-vivo role of matrix molecules in the brain, but also has broad appeal to epilepsy research in general," said Katherine Perkins, PhD, associate professor in the Department of Physiology and Pharmacology at SUNY Downstate.
"More specifically, it should stimulate researchers in the epilepsy field because our study reveals a novel, non-synaptic mechanism of epileptogenesis. The fact that our research can lead to new anti-epileptic therapies based on the preservation of hyaluronan adds further significance for the broader biomedical community and the public," the authors added.
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This research was supported by:
1. National Institutes of Health grants: National Institute of Neurological Disorders and Stroke R56 NS047557 and R01 NS047557 (Hrabetova), National Institute of Neurological Disorders and Stroke R01 NS041332 (Yamaguchi), National Institute of Child Health & Human Development P01 HD025938 (Yamaguchi);
2. Pilot Project award from SUNY Downstate Medical Center College of Medicine's Research Investment Initiative program, (Perkins and Hrabetova);
3. Postdoctoral Supplement award from SUNY Downstate Medical Center College of Medicine's Research Investment Initiative program, (Xiao);
4. Sanford-Burnham Medical Research Institute Investigator Grant (Yamaguchi);
5. Postdoctoral fellowship from the Ministerio de Ciencia e Innovación (MICINN) of Spain (Arranz).
About SUNY Downstate Medical Center
SUNY Downstate Medical Center, founded in 1860, was the first medical school in the United States to bring teaching out of the lecture hall and to the patient's bedside. A center of innovation and excellence in research and clinical service delivery, SUNY Downstate is a major center for neurological research. Downstate comprises a College of Medicine, Colleges of Nursing and Health Related Professions, a School of Graduate Studies, a School of Public Health, University Hospital of Brooklyn, and an Advanced Biotechnology Park and Biotechnology Incubator. SUNY Downstate ranks seventh nationally in the number of alumni who are on the faculty of American medical schools. More physicians practicing in New York City have graduated from SUNY Downstate than from any other medical school. For more information, visit http://www.downstate.edu.
About Sanford-Burnham Medical Research Institute
Sanford-Burnham Medical Research Institute is dedicated to discovering the fundamental molecular causes of disease and devising the innovative therapies of tomorrow. Sanford-Burnham takes a collaborative approach to medical research with major programs in cancer, neurodegeneration and stem cells, diabetes, and infectious, inflammatory, and childhood diseases. The Institute is recognized for its National Cancer Institute-designated Cancer Center and expertise in drug discovery technologies. Sanford-Burnham is a nonprofit, independent institute that employs 1,200 scientists and staff in San Diego (La Jolla), Calif., and Orlando (Lake Nona), Fla. For more information, visit http://www.sanfordburnham.org. Sanford-Burnham can also be found on Facebook at facebook.com/sanfordburnham and on Twitter@sanfordburnham.