NEUROCHEMICAL STUDIES IN GENETIC MODELS OF EPILEPSY

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The purpose of this research is to study the neurochemical, physiological and genetic mechanisms of epilepsy in two different genetic mouse models of epilepsy. These mice include the audiogenic seizure (AGS) susceptible DBA/2 (D2) mouse (a model for generalized absence seizures), and the E1 (epilepsy) mouse (a model for temporal lobe epilepsy). Previous evidence indicates that AGS susceptibility in D2 mice is genetically associated with a deficiency of a brain ecto-Ca2+-ATPase activity. High AGS susceptibility and low brain ecto-Ca2+- ATPase activity are inherited together in Fl hybrids produced from crossing various strains. The biochemical basis for this ecto-Ca2+. ATPase deficiency is presently unknown. To determine if the reduced activity in D2 mice results from a qualitative defect in the enzyme, kinetic properties of the ecto-Ca2+-ATPase will be studied in microsomes and synaptic plasma membranes of the D2 mice and the seizure resistant C57BL/6 (B6) and Fl hybrid mice. We suggest that the ecto-Ca2+. ATPase is essential for the rapid hydrolysis of released ATP and its deficiency in D2 mice contributes to seizure susceptibility by allowing ATP to remain active in the synaptic cleft. This hypothesis is supported from recent studies in B6 and D2 hippocampal slices and will be studied further in B6 x D2 recombinant inbred strains; a powerful analytical tool in mammalian genetics. Preliminary studies also indicate that the major gene for AGS, aspl, is linked to the Ah locus and to a novel restriction fragment length DNA polymorphism on chromosome 12. The relative location of these genes will be mapped using mendelian backcross generations. Since this is the first genetic linkage known between a DNA polymorphism and an epilepsy gene, insight can be obtained on the molecular genetics of epilepsy. An important problem in epilepsy research that has been difficult to resolve concerns the distinction between neurochemical defects associated with the cause of seizures and defects associated with the effects of repeated seizure activity. A paradigm has been developed in E1 mice to deal with this problem. Since our preliminary results show that E1 mice express a reactive gliosis in hippocampus, and elevated content of ganglioside GD3 in cerebellum, and elevated aspartic acid release in hippocampal slices, this paradigm will be used to determine if these defects are elevated aspartic acid release in hippocampal slices, this paradigm will be used to determine if these defects are associated with the cause or effect of seizures. Because the seizures in the D2 and E1 mice occur naturally, the neurochemical defects associated with these seizures will be relevant basic mechanism of epilepsy.