Intractable seizure disorders in humans are often associated with cortical dysplasia, microgyria, and heterotopias resulting from neuronal migration disorders. We have used the rat freeze lesion model to examine neural mechanisms underlying hyperexcitability in focal cortical dysplasia. Our previous studies have shown an involvement of N-methyl-D-aspartate (NMDA) receptors in generation of epileptiform discharges in slices from freeze lesioned animals and have identified changes in potassium channel expression in glial cells. Proposed studies will use whole-cell voltage-clamp recordings from neurons and glial cells to test specific hypotheses about the role of glial potassium currents and glutamate transporters in control of excitability in the dysplastic cortex. Glutamate transporters are important for regulating glutamate levels in the neocortex. It is hypothesized that increases in extracellular glutamate, due to alterations in glutamate transporters, lead to activation of NMDA receptors in dysplastic cortex. It is also hypothesized that changes in potassium channels in glia result in an altered ability to buffer extracellular potassium. Experiments will investigate if decreases in glutamate transporter function make synaptic responses from neurons in dysplastic cortex more sensitive to transporter inhibition than cells from sham operated controls. It will be determined if alterations in transporter function are proconvulsant and if such effects are mediated by NMDA receptors. We will also determine if extracellular glutamate is chronically elevated in dysplastic cortex and if this results in tonic activation of NMDA receptors and a depolarization of neurons. The source of increased extracellular glutamate will be determined by testing the role of action potential dependent release, glutamate transport and cystine-glutamate exchange. Finally, we will determine if the changes in glial ion channel expression we have described are associated with alterations in glutamate transporter current alterations. It is hypothesized that synaptically evoked glutamate tranporter currents in astrocytes differ in their kinetic properties and are reduced. These studies will provide important new information about regulation of extracellular glutamate and .tonic NMDA receptor activation in neocortex. New insights into the role of glutamate transporters in development and regulation of epileptiform activity will be forthcoming. These studies will also increase our understanding of the contribution of glial cells to the intrinsic hyperexcitability observed in freeze-induced focal cortical dysplasia. ? ? ?
Showing the most recent 10 out of 53 publications
