The objective of Project 5 will be to elucidate structural bases of catastrophic childhood epilepsy in human cerebral cortex. the investigation will employ morphological means to: associate patterns of malformation and normal development contributing to pediatric seizure susceptibility, define cellular abnormalities accompanying epileptogenesis, distinguish pathological observations occurring in different seizure disorders and compare most- and least-abnormal sites within an epileptogenic zone of cortical abnormality. Expected results will be significant for understanding the cell biology of epilepsy and the developmental neurobiology of neocortex.
Specific aims derived from preliminary evidence will test hypotheses about correlations between epileptogenesis and structural abnormalities of neocortical neurons including: 1) faulty cytoarchitecture (tissue, junction and cytoskeletal dysmorphogenesis), 2) defective glutamic acid and GABA innervation (transmitter expression, circuit origin and receptor deficits) and 3) abnormal catecholaminergic innervation (modulator expression, circuit origin and receptor anomalies). Morphological studies will be highly collaborative and integral to the Program Project through direct associations of structural and functional disorders. Principal comparisons will be between early and late stages of prospectively defined most- and least-abnormal specimens of cerebral cortex resected surgically from children with catastrophic epilepsy. """"""""Control"""""""" specimens will be from seizure-free age-matched patients receiving cortical resection for other causes, age-matched autopsy cases and similar, but separately funded, studies of developing feline neocortex. The research plan utilizes modern morphological methods based on correlative light and electron microscopy. It assesses neocortical composition (conventional histopathologic stains), fine structure of dendrites, axons and glia (Golgi and biocytin stains) and sites of transmitter, modulator, receptor and cytoskeletal molecules (immunohistochemical stains and fluorescent ligand- binding). All of these methods are known to be productive in human specimens. Rigor and precision of qualitative and quantitative observations will be ensured by multiple labeling and computer-assisted image analysis/morphometry.
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