Epilepsy is a common disorder of the central nervous system, and frequently develops in association with a variety of acquired neuropathological lesions. Kindling refers to the progressive increase in electrographic and behavioral seizures induced by repeated stimulation of certain neural pathways. Although kindling has attracted considerable interest as a model of epilepsy, fundamental issues about its cellular mechanisms and possible relationship to development of seizures after brain lesions are unresolved. Mesial temporal sclerosis (cell loss in hippocampal fields CA3-4 and CA1) is the most common structural lesion associated with epileptic seizures. Recent experiments (see PRELIMINARY STUDIES) have demonstrated that kindling of the entorhinal cortex is dramatically facilitated after destruction of CA3-CA4, a lesion that results in reactive synaptogenesis and reorganization of synaptic inputs to granule cells of the dentate gyrus, the major monosynaptic projection from the entorhinal cortex. This proposal will investigate the hypothesis that facilitated epileptogenesis after a lesion of CA3-CA4 is due to lesion-induced reorganization of hippocampal circuitry. The investigation will utilize quantitative histochemical methods, current source density analysis, and intracellular recording techniques. The proposed experiments will provide insight into epileptic mechanisms in the lesioned hippocampus, cellular mechanisms of kindling, effects of lesion-induced reorganization of synaptic inputs on excitability and integrative properties of dentate granule cells, and mechanisms of seizure development after brain injury.
