Researchers will test if their newly developed molecular imaging biosensor, used in combination with electrical measurements, can identify whether excess amounts of the excitatory neurotransmitter glutamate build up in brain tissue in an animal model of epilepsy.
Epileptic seizures involve the excessive excitability of neurons, and while the excitatory neurotransmitter glutamate is probably involved, scientists do not know how glutamate triggers seizures. A better understanding of this could help the 600,000 people, out of three million in this country, whose epilepsy does not respond to current treatments, and the large number of treated patients who suffer major side-effects. The researchers hypothesize that excess levels of glutamate are produced by a dysfunctional “glutamate-glutamine shuttle.” Ordinarily, via this shuttle, glutamate is released by neurons to be recycled by glia (supportive tissue that nourishes neurons). The glia break down glutamate into glutamine and release it to neurons, which then convert it back to glutamate. The researchers hypothesize that this process is altered in epilepsy, where excessive glutamate builds up and triggers seizures.
They are developing biological sensors that can be used with the molecular imaging technique FRET (fluorescence resonance energy transfer) to detect levels of glutamate, and particularly levels derived from the shuttle process. They plan to further develop the FRET biosensors. Then they will combine the FRET biosensor imaging with measures of electrical signals from glutamate-using neurons in tissue of animals with epilepsy, and determine whether they can obtain direct evidence of alterations in the glutamate-glutamine shuttle.
Significance: If this technology is shown to be feasible, and eventually demonstrates that epileptic seizures occur from an imbalance in the glutamate-glutamine shuttle, the research will have identified a potential new therapeutic target for controlling epileptic seizures.