title: Segregation of seizure traits in C57 black mouse substrains using the repeated-flurothyl model.
abstract: Identifying the genetic basis of epilepsy in humans is difficult due to its complexity, thereby underlying the need for preclinical models with specific aspects of seizure susceptibility that are tractable to genetic analyses. In the repeated-flurothyl model, mice are given 8 flurothyl-induced seizures, once per day (the induction phase), followed by a 28-day rest period (incubation phase) and final flurothyl challenge. This paradigm allows for the tracking of multiple phenotypes including: initial generalized seizure threshold, decreases in generalized seizure threshold with repeated flurothyl exposures, and changes in the complexity of seizures over time. Given the responses we previously reported in C57BL/6J mice, we analyzed substrains of the C57BL lineage to determine if any of these phenotypes segregated in these substrains. We found that the generalized seizure thresholds of C57BL/10SNJ and C57BL/10J mice were similar to C57BL/6J mice, whereas C57BL/6NJ and C57BLKS/J mice showed lower generalized seizure thresholds. In addition, C57BL/6J mice had the largest decreases in generalized seizure thresholds over the induction phase, while the other substrains were less pronounced. Notably, we observed only clonic seizures during the induction phase in all substrains, but when rechallenged with flurothyl after a 28-day incubation phase, ∼80% of C57BL/6J and 25% of C57BL/10SNJ and C57BL/10J mice expressed more complex seizures with tonic manifestations with none of the C57BL/6NJ and C57BLKS/J mice having complex seizures with tonic manifestations. These data indicate that while closely related, the C57BL lineage has significant diversity in aspects of epilepsy that are genetically controlled. Such differences further highlight the importance of genetic background in assessing the effects of targeted deletions of genes in preclinical epilepsy models.
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, New York, United States of America.
authors.forename: Sridhar B
authors.initials: SB
authors.lastname: Kadiyala
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, New York, United States of America.
authors.forename: Dominick
authors.initials: D
authors.lastname: Papandrea
authors.affiliation: Wadsworth Center, Albany, New York, United States of America; Department of Biomedical Sciences, School of Public Health, University at Albany - State University of New York, Albany, New York, United States of America.
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Herron
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, New York, United States of America; Department of Neurology, Albany Medical College, Albany, New York, United States of America.
authors.forename: Russell J
authors.initials: RJ
authors.lastname: Ferland
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000235:genetics*; D005481:Flurothyl / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012640:Seizures / Q000139:chemically induced* / Q000235:genetics; D013045:Species Specificity
chemical_list: D005481:Flurothyl