Most models of epilepsy focus on neurons, which are the brain cells directly responsible for seizures. But targeting neurons with drugs is often ineffective.
That’s why researchers at Washington University School of Medicine in St. Louis were excited to discover that a type of support cell in the brain, called an astrocyte, also plays a critical role in the development of epileptic seizures in a mouse model of tuberous sclerosis complex (TSC). TSC is a genetic disorder that affects about 50,000 Americans, more than half of whom experience frequent, debilitating epileptic seizures.
The team’s most recent study discusses the mechanisms by which these defective astrocytes trigger seizures. If the findings also apply to humans, they could suggest that currently available drugs that affect levels of a brain chemical called glutamate could be more effective in treating TSC and, potentially, other epilepsy disorders.
“This gives us a rational target for seizures in TSC and may explain why many medications fail,” says Michael Wong, M.D., Ph.D., assistant professor of neurology. “Researchers have not given much thought to the role of astrocytes in epilepsy, so hopefully this model will act as a springboard to get people thinking about the relationship between these cells and seizure disorders.”
These findings appear in the August issue of the journal Annals of Neurology. Wong led the study, in collaboration with David H. Gutmann, M.D., Ph.D., the Donald O. Schnuck Family Professor of Neurology.
In the same way that a theatrical performance has both actors and extensive support personnel, neurons are considered to be the brain’s primary, “star” cells, with a variety of support cells that help them function. While most epilepsy models focus on neurons, Gutmann and his colleagues previously discovered that mice whose astrocytes (a type of support cell) lack a gene linked to TSC called TSC1 developed epileptic seizures.
The model represents one of the first animal models of epilepsy that results from a single gene defect; most models require toxic injections or injury to induce epilepsy.
In their latest study, the team began to decipher how a lack of TSC1 in astrocytes triggers neurons to overreact, resulting in a seizure. In particular, they focused on one “housekeeping” role of astrocytes – removal of the chemical glutamate from synapses, the spaces between neurons. Glutamate is the main brain chemical that excites, or activates, neurons and transmits messages from one neuron to the next. With too much glutamate, neurons either become overly excited or die, both of which can trigger seizures.
The group found that mice with astrocytes lacking TSC1 had abnormally low amounts of two glutamate transporters, Glt-1 and GLAST, which are proteins responsible for clearing glutamate from synapses. Moreover, electrical recordings from these astrocytes revealed that the proteins were about 75 percent less active than in astrocytes from normal mice.
“As we understand more about TSC1 in astrocytes, we gain insights into the relationship between astrocytes and neurons,” Gutmann explains. “The model is therefore exciting for two reasons: It gives us an opportunity to understand basic neurobiology and also to find more creative ways to treat patients.”
Wong M, Ess KC, Uhlmann EJ, Jansen LA, Li W, Crino PB, Mennerick S, Yamada KA, Gutmann DH. Impaired glial glutamate transport in a mouse tuberous sclerosis epilepsy model. Annals of Neurology, 54:251-256, August 2003.
Funding from the Tuberous Sclerosis Alliance, the Klingenstein Fund and the National Institutes of Health supported this research.