Quantitative Genetic Study of Maximal Electroshock Seizure Threshold in Mice: Evidence for a Major Seizure Susceptibility Locus on Distal Chromosome 1

• Published in: Genomics (San Diego, Calif.) Vol. 75; no. 1-3; pp. 35 - 42
• Main Authors: Ferraro, Thomas N., Golden, Gregory T., Smith, George G., Longman, Ryan L., Snyder, Robert L., DeMuth, Denis, Szpilzak, Ivanna, Mulholland, Nicole, Eng, Elaine, Lohoff, Falk W., Buono, Russell J., Berrettini, Wade H.
• Format: Journal Article
• Language: English
• Published: San Diego, CA Elsevier Inc 01.07.2001; Elsevier
• Subjects: Animals; Biological and medical sciences; Chromosome 1; Chromosome Mapping; Classical genetics, quantitative genetics, hybrids; Crosses, Genetic; Electroshock; Epilepsy - genetics; Fundamental and applied biological sciences. Psychology; Genetic Markers; Genetic Predisposition to Disease; Genetics of eukaryotes. Biological and molecular evolution; Genotype; maximum electroshock threshold; Mice; Mice, Congenic; Mice, Inbred C57BL; Microsatellite Repeats; Models, Statistical; Pain Threshold; Phenotype; Polymorphism, Genetic; Quantitative Trait, Heritable; Sex Factors; Vertebrata; epilepsy; seizure; polygenic inheritance; mice; quantitative trait; electroshock; Genetic mapping; Animal model; Nervous system diseases; Quantitative character; Epilepsy; Rodentia; Chromosome 1; Threshold dose; Cerebral disorder; Crisis; Quantitative genetics; Vertebrata; Mammalia; Mouse; Central nervous system disease; Electroshock
• ISSN: 0888-7543; 1089-8646
• DOI: 10.1006/geno.2001.6577

We conducted a quantitative trait locus (QTL) mapping study to dissect the multifactorial nature of maximal electroshock seizure threshold (MEST) in C57BL/6 (B6) and DBA/2 (D2) mice. MEST determination involved a standard paradigm in which 8- to 12-week-old mice received one shock per day with a daily incremental increase in electrical current until a maximal seizure (tonic hindlimb extension) was induced. Mean MEST values in parental strains were separated by over five standard deviation units, with D2 mice showing lower values than B6 mice. The distribution of MEST values in B6×D2 F2 intercrossed mice spanned the entire phenotypic range defined by parental strains. Statistical mapping yielded significant evidence for QTLs on chromosomes 1, 2, 5, and 15, which together explained over 60% of the phenotypic variance in the model. The chromosome 1 QTL represents a locus of major effect, accounting for about one-third of the genetic variance. Experiments involving a congenic strain (B6.D2-Mtv7a/Ty) enabled more precise mapping of the chromosome 1 QTL and indicate that it lies in the genetic interval between markers D1Mit145 and D1Mit17. These results support the hypothesis that the distal portion of chromosome 1 harbors a gene(s) that has a fundamental role in regulating seizure susceptibility.