April 9, 1998
La Jolla, CA – Neuroscientists at The Salk Institute showed that mice lacking a specific brain molecule exhibit reduced susceptibility to epileptic-type seizures. The findings suggest that this molecule, GluR6, may be a suitable target for development of new epilepsy drugs.
The findings appear in the April 9 issue of Nature in a study authored by Salk Professor Stephen Heinemann, Ph.D., in collaboration with Salk Professor Fred Gage, Ph.D. and researchers in his laboratory.
In the study, researchers used kainate to induce seizures in mice. Kainate, an analog of the naturally occurring brain transmitter glutamate, is widely-used as a chemical model for human temporal lobe epilepsy because the seizures and patterns of neuronal damage it induces closely resemble those observed in epileptics. The Salk team then created mice that lacked GluR6, a molecule that forms part of a receptor for glutamate, and showed that these mice were less susceptible than normal mice to kainate-induced seizures.
Glutamate is necessary for learning and memory, and its receptors are found throughout the brain; in fact, they may constitute the largest class of brain receptor. More than 80% of nerve cells use glutamate as a messenger to communicate with other cells. Not all the receptors are identical, however; they can be sorted into different classes and the subtle differences between them provide targets for drug development.
Because of glutamate’s global role in the brain, drugs that affect all of its receptors have undesirable side effects, including hallucinations and memory impairment.
“Therefore, we need to pin down the subtypes of receptors that are involved in specific activities, in this case seizure induction, and find drugs that will zero in on them, leaving the other receptors alone,” said Andreas Sailer, Ph.D., co-lead author of the study. “Agents that can block GluR6 in epileptics may prevent or stop seizures and the brain damage they cause.”
Elevated levels of glutamate have also been linked to the brain damage induced in the aftermath of a stroke, and it is possible that GluR6 plays a role in stroke as well.
Co-lead author of the study is Christophe Mulle, Ph.D., formerly at Salk and currently at the CNRS in France. Other Salk authors include Isabel Perez-Otano, Ph.D., Heather Dickinson-Anson, Ph.D., Cornelia Maron and Bernhard Bettler, Ph.D., currently at Novartis in Switzerland. Collaborators include Pablo E. Castillo, Ph.D., at Gral Flores in Uruguay, Ingrid Bureau at the French CNRS, and Jeffrey R. Mann, Ph.D., at the Beckman Research Institute at the City of Hope.
The work was supported by the National Institutes of Health and the McKnight Foundation. Mulle was supported by grants and fellowships from the CNRS, the French MRES, the National Institutes of Health, the Fondation pourt la Recherche Medicale, and the Region Aquitaine. Sailer was supported by the Schweizerische Nationalfond and the Deutsche Forschungsgemeinschaft and Perez-Otano was supported by the Spanish M.E.C.
The Salk Institute for Biological Studies, located in La Jolla, Calif., is an independent nonprofit institution conducting basic science research dedicated to the improvement of human health and improving the quantity and quality of the world’s food supply.
Its two main fields of concentration are neuroscience and molecular-cellular biology and genetics; The Salk Institute was recently ranked the top research institution worldwide in both of these areas by the Philadelphia-based Institute for Scientific Information.
The Salk Institute was founded in 1960 by polio vaccine pioneer Jonas Salk, M.D., with a gift of land from the City of San Diego and the finanancial support of the March of Dimes Birth Defects Foundation. Thomas D. Pollard, M.D., is President and Chief Executive Officer.