Abstracts

The genome sequence availability coupled with efficient chemical mutagenesis and phenotypic screening increases the potential for assigning function to mammalian genes. We recently published [italic]Szt1[/italic] (Yang et al., 2003; [italic]Hum Mol Genet[/italic], 12: 975-984), a mutation detected by the electroconvulsive threshold (ECT) test, hemizygous for two human epilepsy susceptibility genes. This result emboldened us to seek new seizure threshold mutants where seizure phenotype is primary and can be used to improve therapy.
We screened progeny of ENU treated C57BL/6J mice at the 3% response level for minimal clonic ECT seizures using transcorneal electrodes. Mice were further characterized genetically using DNA markers, as well as for other seizure threshold paradigms including maximal ECT (hindlimb extension seizures) and PTZ.
[italic]Szt2[/italic] (seizure threshold-2) was one of three mutants isolated in pilot screens. It has a low seizure threshold in several paradigms, including minimal and maximal ECT, and PTZ. [italic]Szt2[/italic] is semidominant and was mapped to distal Chr 4 in backcrosses with the BALB/cByJ strain. For higher resolution mapping we progeny-tested mice carrying informative recombinations, restricting [italic]Szt2[/italic] to an 11 Mb interval between [italic]D4Mit332[/italic] and [italic]D4Mit124[/italic]. Candidate genes that might be involved in idiopathic seizure phenotype are being evaluated as the critical interval is being reduced further.
[italic]Szt2[/italic] is a single locus mouse mutation with a low threshold in several seizure induction paradigms, including ECT and PTZ. We are close to identifying the genetic defect. Seizure threshold models with discrete genetic defects have the potential to provide practical and meaningful contributions to developing better AED therapies.
[Supported by: grants from the National Institutes of Health (NS40246 and NS31348 to WNF) and a TJL Postdoctoral Fellowship to YY.]