Bidirectional Transfer Between Electrical and Flurothyl Kindling in Mice: Evidence for Common Processes in Epileptogenesis

Abstract

Summary:Purpose: This study sought to determine whether there was a transfer of seizure susceptibility between two models of epileptogenesis, electrical kindling and a newly described model of flurothyl kindling. In this study, we determined the effects of preexposure to one kindling agent on the seizure responsiveness to the other.Methods: Mice were divided into three groups: (a) six mice (FLK) were kindled with flurothyl, rechallenged with flurothyl after a 28-day incubation phase, implanted with olfactory bulb (08) electrodes, and electrically kindled; (b) six mice (ELK) were implanted with OB electrodes, electrically kindled to six stage 5 seizures, and given one flurothyl trial 3 days later and a second flurothyl trial after a 28-day incubation period; and (c) six mice (IMP) were implanted with OB electrodes, tested with flurothyl at the same times as the ELK group, and later electrically kindled.Results: Mice that were previously kindled with flurothyl (FLK) had significantly faster electrical kindling rates to one stage 5 seizure or to six stage 5 seizures compared with animals in the ELK and IMP groups. Mice that were previously exposed to either electrical kindling or flurothyl kindling had significantly diminished latencies to generalized seizure onset (flurothyl-induced seizure thresholds) either before or after a 28-day incubation period compared with the IMP control mice. In addition, both the FLK and ELK groups had significantly increased percentages of mice expressing forebrain-brainstem seizures, compared with the IMP group, following either rechallenge with flurothyl after a 28-day incubation or focal electrical kindling.Conclusions: These findings indicate a near-complete bidirectional transfer between these electrical and flurothyl kindling models. Mice that were previously exposed to either electrical or flurothyl kindling have increased seizure susceptibilities and altered seizure phenotypes when exposed to the other seizure paradigm. Overall, these studies indicate that previous seizures are the critical determinant of the bidirectional transfer of seizure susceptibility observed, and not the electrical or pharmacologic properties of the original kindling agent. Finally, the observation of near identity in transfer characteristics between electrical and flurothyl kindling models suggests that the proepileptogenic processes initiated by exposure to either model are similar.

Spatiotemporal differences in the c-fos pathway between C57BL/6J and DBA/2J mice following flurothyl-induced seizures: A dissociation of hippocampal Fos from seizure activity

“…1) as has been previously described (Ferland and Applegate, 1999, Franck, et al, 1989, Hashimoto, et al, 2006, Oommen, et al, 2007, Papandrea, et al, 2009, Samoriski and Applegate, 1997, Stafstrom, et al, 1992); however, concentrations of flurothyl necessary for generalized seizure expression are also reported (Table 1). All C57BL/6J (B6) mice tested in the repeated-flurothyl model had a high initial latency to generalized seizure expression compared to DBA/2J (D2) mice, which significantly decreased over the course of eight repeated flurothyl exposures, plateauing on seizure trial 5 (Fig.…”

“…The repeated-flurothyl model is a seizure paradigm that uses the chemoconvulsant flurothyl to examine seizure susceptibility and epileptogenesis (Applegate, et al, 1997, Ferland and Applegate, 1999, Samoriski and Applegate, 1997). In this model, mice are given 8 flurothyl-induced seizures, one per day, for 8 days.…”

“…Following a 28 day rest period and final flurothyl rechallenge, 70–90% of B6 mice display a new seizure type characterized by a generalized clonic seizure that secondarily generalizes into a brainstem seizure (denoted as a forebrain→brainstem seizure) (Applegate, et al, 1997, Ferland and Applegate, 1999, Samoriski and Applegate, 1997). The emergence of this new, more complex seizure phenotype with time suggests an underlying evolution of an epileptogenic process (Applegate, et al, 1997, Ferland and Applegate, 1999, Samoriski and Applegate, 1997), and involves the recruitment of new structures into the seizure propagation network necessary for the expression of a more complex seizure phenotype (Ferland and Applegate, 1998). Thus, the repeated-flurothyl model serves as an important paradigm for elucidating brain structures and mechanisms involved in changes in seizure complexity/severity over time and epileptogenesis.…”

Seizure Susceptibility, Phenotype, and Resultant Growth Delay in the nclf and mnd Mouse Models of Neuronal Ceroid Lipofuscinoses

“…This phenotypic switch following flurothyl-kindling has been proposed to result from synaptic reorganization. 11–12 An absence of this phenotypic switch in the nclf and mnd mice indicates there may be shared disruption and reorganization of seizure-related neuroanatomical pathways in the brainstem among the neuronal ceroid lipofuscinoses.…”

“…Seizures were induced by placing mice individually into a 2.4-liter closed Plexiglas chamber into which a 10% solution of flurothyl (2,2,2-trifluroethyl ether; Sigma-Aldrich, St. Louis, Missouri) was infused as previously described. 11 Animals were weighed immediately post-seizure. For kindling studies, generalized seizures were induced once a day for 8 consecutive days (Induction Phase) with subsequent retesting once a week for 4 weeks (Incubation Phase).…”