This multidepartment and multidisciplinary investigative effort on basic mechanisms of human epilepsies evolved in response to the needs and referral patterns of the community of Los Angeles to the California Comprehensive Epilepsy Program. Two component projects supported by clinical and tissue utilization functions of Core Units B and D, examine the multifactorial mechanisms of temporal lobe hippocampal epilepsy and sclerosis: Project 1 is piecing together the molecular and systems anatomy of hippocampal sclerosis and studying the ultrastructural characteristics of aberrant dynorphin positive structures in the inner molecular layer of the dentate gyrus, by measuring pro-dynorphin mRNA in abnormally aligned granule cells, and by utilizing retrograde tracer diI to understand the reorganized circuitry of the hippocampal formation. Project 2 is also focusing on differential distribution of GABAA receptor subtypes in the hippocampus of temporal lobe epilepsy. Project 2 evaluates the role of viruses in the pathogenesis of the complex partial epilepsies. It continues the search for genomic sequences of HSV-1 by the PCR-""""""""DNA amplification"""""""" technique in Rasmussen's focal epilepsy and hippocampal epilepsy preceded by limbic encephalitis or febrile convulsions. Component Project 3 works in concert with the family studies unit of Core C to further localize the gene of Juvenile Myclonic Epilepsy (JME) which we recently linked to the Bf and HLA region of the short arm of chromosome 6. Phenotypic markers, HLA and restriction fragment length polymorphisms (RFLPs) are used to screen pedigrees of JME, absence, and grand mal tonic- clonic epilepsies to answer the questions of heterogeneity within JME, itself, and amongst absence and grand mal epilepsies. Our second objective for Component Project 3 is to identify markers that flank the JME locus. We will use HLA serologic markers and RFLPs, located in areas within and around the HLA region, during genetic linkage analysis. The eventual aim is to microlocalize the JME gene to the smallest co- segregating region (approximately a 2 centimorgan interval between a pair of flanking markers).
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