Vesicular Zinc of Recurrent Mossy Fiber in Epilepsy

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Epilepsy is a chronic neurological condition that affects about 1% of the population in the United States. Although it is usually treatable with medications, about 25-30% of epileptic patients continue to experience recurrent seizure in spite of multiple drug therapy. The dentate gyrus (DG) normally functions as a filter. It prevents propagation of synchronized activity into the seizure-prone hippocampus. This filter or 'gatekeeper' attribute of the DG is compromised in temporal lobe epilepsy (TLE). In TLE, Mossy fibers (MF), the axons of granule cells, frequently sprout and aberrantly innervate the somatic and inner molecular layers of DG. Recurrent MF mediates reverberating excitation that can reduce the threshold for granule cell synchronization and, presumably facilitating participation of the DG in seizures. Recurrent MFs are known to be critically involved in temporal lobe epilepsy but they are only poorly understood. Unique property of MF is that they contain high concentrations of zinc (Zn2+), which is colocalized in synaptic vesicles and co-released with glutamate. Zn2+ has been implicated modulatory effects on a variety of ion channels, including attenuation of current through NMDA and GABA receptor-gated channels. In this study, pilocarpine-treated rats which become epileptic and develop a consistently dense recurrent MF pathway will be used to investigate and characterize the release of Zn2+ from recurrent MF about, which little information is available. We will also determine the translocation of MF released Zn2+ into granule cells. Proposed experiments are based on our previously published data and preliminary studies which have led to the need to complete these proposed highly feasible experiments. The outcome of the study will build foundation for future study on the action of released Zn2+ on neurotransmission as well as involvement of recurrent MF in TLE. The results will facilitate development of more rational, informed or targeted therapeutic strategies for epilepsy.