This multidepartment, multi-instituite investigative effort on the basic mechanisms of human epilepsies evolved from the UCLA Comprehensive Epilepsy Program. It consists of nine component projects which examine the multifactorial mechanisms of temporal lobe epilepsies and the genetic mechanisms of benign juvenile myoclonic epilepsy. The first three projects examine the ion transport pathways of synaptic terminals and glial cells in lobectomy specimens of human temporal lobe epilepsies. (Na+K+)-ATPase, (Ca2+)-ATPase and ecto-ATPase activities are correlated in synapses and glial cells. The role of phosphorylation of brain membrane proteins with molecular weights of 18 K, 50-60 K, and 80 K in membrane permeability and depolarization is also studied in the lobectomy specimens. Biochemical and transport mechanisms of GABA and glutamate are further examined in synaptic terminals and glial cells. Ionic channels coupled to the GABA receptor are dissected in Project 4 by patch clamp recordings of single channel currents in dissociated cell cultures of hippocampus excised from lobectomy specimens. Project 5 assesses post-synaptic mechanisms of GABA actions; receptor binding sites for GABA and benzodiazepines are quantitated in homogenates of temporal lobectomy specimens. To provide a functional and morphological picture of neurons that use GABA or acetylcholine as neuroactive subsstances, the organization of GABA and Ach neurons in amygdala of anterior temporal lobectomy specimens are visualized by immunocytochemistry in Project 6. Animal experiments examine acquired and genetic epilepsies in Projects 1 to 6 and provide directions of research thrusts and new testable hypotheses for human temporal lobe epilepsies and juvenile myoclonic epilepsy. Projects 7 and 8 seek the chromosomal locus of juvenile myoclonic epilepsy by linkage analysis with 31 phenotypic blood markers and 20 restriction fragment length polymorphisms. Project 9 is developing candidate gene markers for human epilepsies and plans to engineer new genetic models of epilepsy by blocking the expression of genes for glutamic acid decarboxylase or GABA receptors. Through these nine mutually reinforcing component projects, new insights into the molecular mechanisms of acquired biochemical lesions and the epilepsy susceptibility gene of human epilepsies will be acquired.
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