This project aims to study (1) the neuroanatomic reorganization of epileptogenic brain regions in patients with medically intractable temporal lobe epilepsy (TLE), and (2) the consequence of heat-induced (febrile) seizures in the development of hippocampal pathology in a rat seizure model. Most patients with TLE present one of two conditions: a lesion or mass (commonly a tumor) as the seizure focus (referred to as tumor-related TLE--TTLE); or no lesion but an abnormally organized hippocampus (referred to as cryptogenic temporal lobe epilepsy--CTLE). Removal of either of these foci produced good seizure control. The specific hypothesis for this investigation is that the key to the mechanism of epileptogenicity is contained within the morphological and biochemical reorganization of the removed seizure focus. In medial temporal lobe (hippocampal) seizure foci the microcircuitry of the epileptogenic hippocampal area dentate will be further defined by light microscopic morphometry of silver impregnated or dye filled (Lucifer Yellow or biocytin) neurons, with an immunocytochemical and electronmicroscopic analysis of their chemically defined synaptology. The subiculum and entorhinal cortex of CTLE patients will be studied with cell counts, neural spine morphometries, immunocytochemistry and receptor autoradiography to determine if progressive deterioration in organization of the hippocampus results in reorganization of the subiculum and/or entorhinal cortex. In neocortical tumor foci (temporal and extratemporal lobe in location) in TTLE, the regions of brain around epileptogenic tumors will be studied with immunocytochemistry and receptor autoradiography to determine if there is neuroanatomic reorganization around a tumor indicative of a hyperexcitable substrate. Glia in tissue and cell cultures established from hippocampal and neocortical tumor foci, will be stained with glial and neuronal markers, to define their neuroanatomic characteristics. In rat pups induced to seizures by repeated exposure to warm water, the neuronal and neurochemical organization in relation to excitatory and inhibitory amino acids and their receptors (Glutamate, Gamma aminobutyric acid); the neuropeptides somatostatin, neuropeptide Y and dynorphin; and calcium binding proteins will be studied by immunocytochemistry and receptor autoradiography to define the degree of seizure-related hippocampal reorganization.
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