The dentate gyrus provides the primary input to the hippocampus proper via the perforant path and has been implicated in the pathogenesis of certain types of human and animal epilepsy. However, the electrophysiological characteristics of the cells found in this region are poorly understood. This proposal is designed to examine the electrophysiological properties of cells from human and rodent dentate gyri. The human tissue used in this study is biopsy tissue from patients with medically intractable epilepsy and falls into two categories: those with medial temporal lobe sclerosis in which a number of biochemical and histological markers in the hippocampus are affected, and those with lesions or tumors in the temporal lobe in which these markers are relatively unaffected. All the experiments outlined below will be performed in parallel in rodent tissue. The hippocampi are maintained as 400 micrometer slices in an in vitro recording chamber and electrophysiological recording and cell labelling techniques will be used. The broad goals of this project are to determine if specific changes, at the level of single cells, can be seen in epileptic tissue relative to the comparison human tissue and to rodent controls. Our specific goals include: first, to classify the morphological and electrophysiological characteristics of both the granule cells and interneurons found in the dentate for the two types of human tissue as well as for rodents; second, to study the exciatory and inhibitory properties and their modulation in these three types of tissue and third to assess the actions of a number of peptide neurotransmitters which are affected in cases of temporal lobe sclerosis. A significant portion of this proposal is devoted to studying the modulation of the NMDA type glutamate receptor in the three classes of tissue. This receptor appears to underlie epileptiform activity in a number of animal epilepsy models and thus changes in the modulation of this receptor subtype are candidates for the hyperexcitability seen in the sclerotic tissue. Three modulators will be examined in detail: extracellular pH, Zn, and Mg.
