The long term objective of this research is to better define the genetic and neurochemical basis of seizure susceptibility in the epileptic EL mouse. The EL mouse is considered a genetic model for temporal lobe epilepsy. Although seizure susceptibility in EL mice is inherited as a multifactorial trait, most of the genetic variability for this susceptibility is regulated by the major El-1 gene. El-1 was recently mapped to the distal region of chromosome 9 between the dilute/short ear and B-galactosidase loci. A novel system of polymorphic DNA markers, called simple sequence repeat polymorphisms (SSLPs) will be used to more precisely map El-1 within this interval. These SSLPs are rapidly typed from DNA preparations using the polymerase chain reaction (PCR). El-1 mapping will be performed in unique interval congenic strains and in F2 and backcross generations from crosses of EL with the exotic wild mouse strain, CAST. The interval congenic strains are constructed to contain either the dominant El-1 seizure gene in nonseizure genetic backgrounds or the recessive normal gene in the EL seizure background. The interspecific cross with CAST will generate numerous DNA polymorphisms for precisely mapping El-1. The region of chromosome 9 containing El-1 is highly conserved with a region on human chromosome 3q containing the ceruloplasmin (Cp) and transferrin (Trf) genes. Recent preliminary results show the coinheritance of EL seizures with Cp and Trf polymorphisms. These polymorphisms can serve as new genetic markers for more precisely mapping El-1. Neurochemical studies will involve analysis of endogenous neurotransmitter release and GFAP content in hippocampal slices from seizure susceptible and resistant mouse strains. Recent findings suggest that enhanced aspartate release is genetically associated with EL seizures and that hippocampal GFAP content is associated with the effects, rather than cause, of seizure activity. Neurotransmitter release and GFAP content will be analyzed further using HPLC and Western blot/immunostaining, respectively. These proposed studies can provide a better understanding of basic epilepsy mechanisms in both the mouse and man.
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