Mutation Screens for Mouse Models with Altered Electroconvulsive Threshold
Abstract number :
3.023
Submission category :
Year :
2001
Submission ID :
356
Source :
www.aesnet.org
Presentation date :
12/1/2001 12:00:00 AM
Published date :
Dec 1, 2001, 06:00 AM
Authors :
W.N. Frankel, The Jackson Laboratory, Bar Harbor, ME; L. Taylor, Pharmacology and Toxicology, University of Utah, Salt Lake City, UT; B. Beyer, The Jackson Laboratory, Bar Harbor, ME; H.S. White, Pharmacology and Toxicology, University of Utah, Salt Lake
RATIONALE: The imminent mouse genome sequence coupled with the efficiency of random mutagenesis and direct phenotypic screening increases the potential for assigning function to mammalian genes. We are interested in finding genes for new single gene mouse mutations where seizure susceptibility is primary and in the development of new experimental models can be used to evaluate and improve therapies.
METHODS: Our screen is based on electroconvulsive threshold (ECT) - a standard for screening antiepileptic drugs (AED) in mice. We determine ECT in a panel of strains and then whether strains respond differently to an AED at a set threshold. Then we screen for mutants with abnormal ECT and further characterize them for AED response and other seizure phenotypes.
RESULTS: We examined more than 14 mouse strains in 3 ECT paradigms (minimal clonic; maximal tonic hindlimb extension; psychomotor), and AED responses in a few strains. Although C57BL/6J was always the most resistant strain, and DBA/2J usually the most sensitive, a range of responses in other strains suggests a diverse array of modifier genes. Several strains had intruiging ECT profiles, including FVB and CBA/J, which had similar sensitivities to minimal and psychomotor seizures but the latter was relatively resistant to maximal seizures. In initial mutation screens of ENU-mutagenized C57BL/6J mice, several new mouse mutants with low ECTs have now been obtained. Two of these have been chromosomally mapped: Ect1, a dominant mutation which maps to the telomeric region of mouse Chr 2 near Chrna and Kcnq2; and Ect2, a recessive mutation on distal Chr 4. Several additional heritable recessive mutations with low ECT are presently under characterization, and potential mutations with high ECT (relatively resistant) are being tested for inheritance.
CONCLUSIONS: The ECT test is suitably robust for the screening of new heritable, mappable mouse mutations which can then be characterized on isogenic backgrounds without the complications of polygenic models. The fact that the primary screen, ECT, is designed for AED screens provides hope that these new models may be valuable not only for understanding of neuroexcitability but also for improvement of drug therapies.
Support: NIH Grant NS40246