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The Journal of Neuroscience, August 15, 1999, 19(16):6733-6739

Mapping Loci for Pentylenetetrazol-Induced Seizure Susceptibility in Mice

Thomas N. Ferraro^{1, 2}, Gregory T. Golden^{1, 4}, George G. Smith^{1, 4}, Pamela St. Jean⁵, Nicholas J. Schork^{5, 6, 7, 8}, Nicole Mulholland¹, Christos Ballas¹, Jörg Schill¹, Russell J. Buono¹, and Wade H. Berrettini^{1, 3}

Departments of ¹ Psychiatry, ² Pharmacology, and ³ Genetics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, ⁴ Research Service, Department of Veterans Affairs Medical Center, Coatesville, Pennsylvania 19320, Departments of ⁵ Biostatistics and Genetics and ⁶ Epidemiology, Case Western Reserve University, Cleveland, Ohio 44106, ⁷ Department of Biostatistics, Harvard University, Boston, Massachusetts, and ⁸ The Jackson Laboratory, Bar Harbor, Maine 04609

DBA/2J (D2) and C57BL/6J (B6) mice exhibit differential sensitivity to seizures induced by various chemical and physical methods, with D2 mice being relatively sensitive and B6 mice relatively resistant. We conducted studies in mature D2, B6, F1, and F2 intercross mice to investigate behavioral seizure responses to pentylenetetrazol (PTZ) and to map the location of genes that influence this trait. Mice were injected with PTZ and observed for 45 min. Seizure parameters included latencies to focal clonus, generalized clonus, and maximal seizure. Latencies were used to calculate a seizure score that was used for quantitative mapping. F2 mice (n = 511) exhibited a wide range of latencies with two-thirds of the group expressing maximal seizure. Complementary statistical analyses identified loci on proximal (near D1Mit11) and distal chromosome 1 (near D1Mit17) as having the strongest and most significant effects in this model. Another locus of significant effect was detected on chromosome 5 (near D5Mit398). Suggestive evidence for additional PTZ seizure-related loci was detected on chromosomes 3, 4, and 6. Of the seizure-related loci identified in this study, those on chromosomes 1 (distal), 4, and 5 map close to loci previously identified in a similar F2 population tested with kainic acid. Results document that the complex genetic influences controlling seizure response in B6 and D2 mice are partially independent of the nature of the chemoconvulsant stimulus with a locus on distal chromosome 1 being of fundamental importance.

Key words: seizure; quantitative trait loci; epilepsy; mice; pentylenetetrazol; genetics

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Copyright © 1999 Society for Neuroscience  0270-6474/99/19166733-07$05.00/0

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