Glutamate and lactate: Jason-faced actors in neurology

Excitatory amino acids play dual roles in the brain: they are physiological transmitters but have the potential to damage brain tissue. The same may be true for lactate, an important intermediate in cell metabolism. The project will study the roles of exc itatory amino acids and lactate transport in normal synaptic transmission and test whether they are involved in the development of brain diseases, such as epilepsy and stroke. To our disposal are knock-out mice for synapsins and a vesicular glutamate tran sporter (VGLUT3). The study will make use of the intact rat brain, in vitro brain slice preparations and experimental models for stroke, as well as human epileptic brain tissue (removed as part of surgical treatment for epilepsy). In particular, by using immunocytochemical methods, including quantitative electron microscopic immunogold cytochemistry, and electrophysiological techniques (international collaboration), the project will seek to answer the following questions: What are the mechanisms underlyin g the propensity for seizures in synapsin knock-out mice, despite their impaired synaptic function? May MCT2 and MCT4 activity modulate excitatory amino acid transmission? Does glutamate contribute to signalling at the neuromuscular junction, and what is the role of VGLUT3 at this site? Is aspartate involved in the pathogenesis of epilepsy? Are MCTs involved in the pathogenesis of epilepsy and stroke? What are the cellular and molecular mechanisms of action of the widely used anti-epileptic drug valproate ? The knowledge gained will provide new insight in disease mechanisms and may lead to new therapeutic and diagnostic measures in neurology.