PATHOPHYSIOLOGY OF DEVELOPING DYSPLASTIC HUMAN CORTEX

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Based on neuroimaging (MRI and PET) and examination of surgically-resected tissue, cortical dysplasia (CD) has become recognized as a major pathological substrate in epilepsy. UCLA's Pediatric Epilepsy Surgery Program treats populations of children with intractable seizures, and in our experience one-half of the cases have CD while the remaining have etiologies such as strokes and encephalitis (non-CD). Very little is known about the electrophysiological properties of cells in dysplastic cortex, the underlying mechanism(s) that make CD and non-CD areas epileptogenic, and how normal postnatal cortical development affects epileptogenic neocortex. This research project is designed to address these fundamental pathophysiologic questions by performing coordinated morphologic and electrophysiologic studies on surgical tissue from these children. Our working hypothesis is that abnormal neocortex is epileptogenic because of an imbalance between excitatory and inhibitory processes and that cortical axon circuits are abnormally organized as a consequence of the pathologic process. The proposed studies will have two goals: 1) To examine the hypothesis that excitatory and inhibitory processes are altered in CD and non-CD tissue; and 2) to assess development of excitatory and inhibitory processes in neocortical neurons during human postnatal development. Each specific aim will utilize a similar experimental design incorporating pre-surgical clinical and intraoperative ECoG to determine which regions are to be studied for intracellular electrophysiology and morphologic assessments. Using state-of-the-art morphologic and electrophysiologic techniques, experiments will compare "abnormal"-appearing neurons in CD and non-CD neocortex to determine: 1) If there are differences and/or alterations in N-methyl-D-aspartate (NMDA) and non-NMDA alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainate (KA)] ionotropic glutamate receptors; 2) if there are differences in the number of inhibitory neurons and/or an increase in inhibitory GABAA receptors; and 3) if one possible etiology of seizures in the tissue is from abnormal axon circuitry. These goals will be accomplished by examining in visually-identified dysplastic and normal-appearing cells: 1) The alterations in electrophysiologic membrane currents induced by activation of NMDA, AMPA, KA, and GABAA receptors; 2) the number and location of neurons expressing NMDA, non-NMDA, and GABAA subunits using in situ hybridization and immunohistochemical techniques; and 3) the dendritic and axonal connections as identified by filling recorded dysplastic neurons and normal-appearing cells with biocytin or Lucifer Yellow. The findings will provide important fundamental information necessary for the understanding of the pathophysiology of dysplastic neocortex, suggest pathologic mechanisms of intractable childhood epilepsy, and provide insights into possible ways of controlling childhood seizures resulting from CD and non-CD.