GENETICS,MOLECULAR BIOLANDPHARMACOLOGICS--EPILEPSY GENES

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Frings audiogenic seizure (AGS)-susceptible mice represent a genetic model of sensory-evoked reflex epilepsy which, unlike the DBA/2J AGS-susceptible mouse, displays a life-long susceptibility to sound-induced seizures. Breeding studies have demonstrated that the Frings phenotype is a monogenic and highly penetrant autosomal recessive trait; whereas, the DBA/2J seizure phenotype is polygenic in origin and results from at least three known loci (i.e., asp1, asp2, and asp3). We have mapped the monogenic audiogenic seizure-susceptible (mass1) locus of the Frings mouse to an approximately 2 cM region on chromosome 13. The identification and characterization of the disease gene in this simple monogenic mouse epilepsy model will add new insight into the pathophysiology of more complex human seizure disorders. The four SPECIFIC AIMS outlined in this proposal will begin to test this hypothesis. The fine mapping studies of SPECIFIC AIM 1 will narrow the mass1 locus and thereby expedite the cloning process. The physical mapping studies outline in SPECIFIC AIM 2 will provide the foundation for the identification of candidate cDNAs and expressed sequence tags (ESTs) which will ultimately lead to the cloning of the mass1 gene. The breeding strategies employed in SPECIFIC AIM 3 will place the mass1 gene onto well-characterized AGS-resistant (C57BL) and AGS-sensitive (DBA/2J) backgrounds to construct new congenic mouse strains. These new congenic strains will be useful for identifying interactions between the mass1 gene and other seizure-susceptibility and seizure-resistance genes. The pharmacologic and phenotypic consequences of placing the mass1 gene on different genetic backgrounds will be characterized in SPECIFIC AIM 4 wherein the AGS-susceptibility and seizure-threshold of mice from the new congenic strains will be evaluated. These studies will provide new insight into the pathophysiologic basis of genetic epilepsy and provide new molecular targets that will be useful for rational antiepileptic drug development and gene therapy.