The objective of this project is to elucidate the neural substrate underlying neural hyperexcitability in human temporal lobe epilepsy (TLE). In a subset of TLE patients referred to as Cryptogenic Temporal Lobe Epilepsy (CTLE) patients the seizure focus is determined, on the basis of prior electrode recordings, to be the hippocampus. Analysis of the neural organization of the hippocampus in CTLE patients in comparison to its organization in subjects with no hippocampally generated seizures has provided and could provide more important data on the neural mechanisms supporting hyperexcitability. The specific hypothesis for this investigation is that the key to the mechanism of epileptogenicity of the hippocampal seizure focus is contained within its morphological and biochemical reorganization, in particular the fascia dentata region. To define the neuronal microcircuitry of this region the morphology of fascia dentata neurons impregnated with silver, filled with Lucifer Yellow, HRP or Biocytin (with project VII) will be analyzed by light microscopic morphometric techniques; and the normal and chemically defined synaptology of identified neurons studied with immunocytochemistry and electron microscopy. The existence of new axonal pathways in CTLE for passage of granule cell excitation out of the hippocampus will be examined with axon tracing methods in hippocampal slices using the carbocyanine dye DiI, and HRP or Biocytin (with project VII). The hippocampal reorganization will be assessed by studying the distribution of these neurotransmitters and their receptors with immunocytochemistry and receptor autoradiography respectively. Clues to mechanisms of selective vulnerability of subgranular somatostatin and neuropeptide Y interneurons in CTLE will be sought in an examination of other chemical markers of these neurons by double labeling studies. The hypothesis that microdysgenesis is a morphological characteristic of TLE will be evaluated through morphometric studies of ectopic neurons in the molecular layer of the neocortex and subcortical white matter. The identification of the neuromorphological and neurochemical substrate of epileptogenicity is important for both careful physiological studies and for the rational development of new drugs to treat this hitherto medically intractable disease.