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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.
Highlights
While mapping seizure-related quantitative trait loci (QTL) and identifying genes responsible for modifying baseline seizure threshold has been successful in rodents [1,2,3,4,5,6,7,8,9], discovery of genes beyond initial seizure threshold remains challenging
Given the unique seizure characteristics of C57BL/6J (6J) mice [11,12,26,32,33], we examined substrains of C57BL mice to determine their initial myoclonic jerk threshold (MJT; as determined by the latency from the start of flurothyl infusion to the appearance of myoclonic jerks [12,29]), decreases in MJT with repeated flurothyl exposures, initial generalized seizure threshold (GST; as determined by the latency from the start of flurothyl infusion to the expression of a generalized seizure [11,12,26,32,33]), decreases in GST with repeated flurothyl exposures, and the evolution of more complex seizure phenotypes over time
We have shown that myoclonic jerk thresholds are significantly different between 6J mice and other inbred strains [29], so here we examined whether differences were observed between C57BL substrains
Summary
While mapping seizure-related quantitative trait loci (QTL) and identifying genes responsible for modifying baseline seizure threshold has been successful in rodents [1,2,3,4,5,6,7,8,9], discovery of genes beyond initial seizure threshold (e.g., changes in seizure threshold over time, development of more complex seizures, and/or epileptogenesis) remains challenging. The greatest advantage of the repeated-flurothyl model is that this paradigm results in a progression of seizure behaviors that begin as clonic seizures, but change over time to seizures with tonic manifestations This change in seizure complexity, which involves the interaction of two independent seizure expression networks (the forebrain and brainstem seizure networks [12,14,15,16,17,18,19,20,21]), is not observed in other kindling models. This alteration in seizure phenotype allows for the dissection of genes and mechanisms that are responsible for the propagation of ictal discharge from the forebrain seizure circuitry mediating clonic seizure expression to the brainstem seizure circuitry that mediates tonic seizure expression This aspect of the repeated-flurothyl model is unique in that it provides a framework for better understanding why humans with epilepsy can develop more complex seizures over time [22,23,24,25]. The recent elucidation of the importance of subcortical structures in the expression of generalized seizures in the human epileptic population supports the importance of understanding the molecular processes controlling this phenotype in this preclinical model [27,28]
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