Eight Flurothyl-Induced Generalized Seizures Lead to the Rapid Evolution of Spontaneous Seizures in Mice: A Model of Epileptogenesis with Seizure Remission

Ferraro

2017

Epilepsy & Behavior

It is becoming increasingly clear that the genetic background of mice and rats, even in inbred strains, can have a profound influence on measures of seizure susceptibility and epilepsy. These differences can be capitalized upon through genetic mapping studies to reveal genes important for seizures and epilepsy. However, strain background and particularly mixed genetic backgrounds of transgenic animals need careful consideration in both the selection of strains and in the interpretation of results and conclusions. For instance, mice with targeted deletions of genes involved in epilepsy can have profoundly disparate phenotypes depending on the background strain. In this review, we discuss findings related to how this genetic heterogeneity has and can be utilized in the epilepsy field to reveal novel insights into seizures and epilepsy. Moreover, we discuss how caution is needed in regards to rodent strain or even animal vendor choice, and how this can significantly influence seizure and epilepsy parameters in unexpected ways. This is particularly critical in decisions regarding the strain of choice used in generating mice with targeted deletions of genes. Finally, we discuss the role of environment (at vendor and/or laboratory) and epigenetic factors for inter- and intrastrain differences and how such differences can affect the expression of seizures and the animals’ performance in behavioral tests that often accompany acute and chronic seizure testing.

Section: Interstrain Differences In the Expression Of Seizures Andmentioning

confidence: 84%

The relevance of inter- and intrastrain differences in mice and rats and their implications for models of seizures and epilepsy

Löscher¹,

Ferraro

2017

Epilepsy & Behavior

“…Additionally, local field potential recordings from the cerebral cortex and hippocampus of C57BL6/J mice, during the 28-day incubation period, reveals that flurothyl-exposed mice develop spontaneous seizures following the 8 th flurothyl induction trial with relatively high seizure occurrences (Kadiyala et al , 2016). However, these seizures begin to remit over the 28-day incubation phase (Kadiyala et al , 2016).…”

Section: Methodsmentioning

confidence: 99%

“…However, these seizures begin to remit over the 28-day incubation phase (Kadiyala et al , 2016). Interestingly, DBA/2J mice similarly treated also develop spontaneous seizures with fewer seizure occurrences than C57BL6/J mice, but the spontaneous seizures observed in DBA/2J mice do not appear to remit (Kadiyala and Ferland, 2017).…”

Section: Methodsmentioning

confidence: 99%

“…We refer to these seizures as forebrain→brainstem seizures denoting the ictal progression from the forebrain seizure network to the brainstem seizure network (Papandrea et al ., 2009; Kadiyala et al ., 2015). Lastly, C57BL6/J mice exposed to the repeated flurothyl seizure model rapidly develop spontaneous seizures that appear to remit without treatment following 1 month (Kadiyala et al ., 2016), in contrast to DBA2/J mice which also rapidly develop spontaneous seizures that do not remit (Kadiyala and Ferland, 2017). Here, we describe the methods for assaying mice in the repeated flurothyl seizure model, which was originally described 20 years ago (Applegate et al ., 1997; Samoriski and Applegate, 1997) and continues to be characterized.…”

Section: Introductionmentioning

confidence: 99%

“…This work was adapted from previous publications (Samoriski and Applegate, 1997; Kadiyala et al , 2016). …”

mentioning

confidence: 99%

See 2 more Smart Citations

The Repeated Flurothyl Seizure Model in Mice

2017

BIO-PROTOCOL

Development of spontaneous seizures is the hallmark of human epilepsy. There is a critical need for new epilepsy models in order to elucidate mechanisms responsible for leading to the development of spontaneous seizures and for testing new anti-epileptic compounds. Moreover, rodent models of epilepsy have clearly demonstrated that there are two independent seizure systems in the brain: 1) the forebrain seizure network required for the expression of clonic seizures mediated by forebrain neurocircuitry, and 2) the brainstem seizure network necessary for the expression of brainstem or tonic seizures mediated by brainstem neurocircuitry. In seizure naïve animals, these two systems are separate, but developing models that can explore the intersection of the forebrain and brainstem seizure systems or for elucidating mechanisms responsible for bringing these two seizure systems together may aid in our understanding of: 1) how seizures can become more complex overtime, and 2) sudden unexpected death in epilepsy (SUDEP) since propagation of seizure discharge from the forebrain seizure system to the brainstem seizure system may have an important role in SUDEP because many cardiorespiratory systems are localized in the brainstem. The repeated flurothyl seizure model of epileptogenesis, as described here, may aid in providing insight into these important epilepsy issues in addition to understanding how spontaneous seizures develop.

Dissociation of spontaneous seizures and brainstem seizure thresholds in mice exposed to eight flurothyl‐induced generalized seizures

Kadiyala

2016

Epilepsia Open

Summary Objective C57BL/6J mice exposed to eight flurothyl-induced generalized clonic seizures exhibit a change in seizure phenotype following a 28-day incubation period and subsequent flurothyl rechallenge. Mice now develop a complex seizure semiology originating in the forebrain and propagating into the brainstem seizure network (a forebrain→brainstem seizure). In contrast, this phenotype change does not occur in seizure-sensitive DBA/2J mice. The underlying mechanism(s) was the focus of these studies. Methods DBA2/J mice were exposed to eight flurothyl-induced seizures (1/day) followed by 24-hour video-electroencephalographic recordings for 28-days. Forebrain and brainstem seizure thresholds were determined in C57BL/6J and DBA/2J mice following one or eight flurothyl-induced seizures, or after eight flurothyl-induced seizures, a 28-day incubation period, and final flurothyl rechallenge. Results Similar to C57BL/6J mice, DBA2/J mice expressed spontaneous seizures. However, unlike C57BL/6J mice, DBA2/J mice continued to have spontaneous seizures without remission. Because DBA2/J mice do not express forebrain→brainstem seizures following flurothyl rechallenge after a 28-day incubation period, this indicated that spontaneous seizures were not sufficient for the evolution of forebrain→brainstem seizures. Therefore, we determined whether brainstem seizure thresholds were changing during this repeated-flurothyl model and whether this could account for the expression of forebrain→brainstem seizures. Brainstem seizure thresholds were not different between C57BL/6J and DBA/2J mice on day one or on the last induction seizure trial (day eight). However, brainstem seizure thresholds did differ significantly on flurothyl rechallenge (day 28) with DBA/2J mice showing no lowering of their brainstem seizure thresholds. Significance These results demonstrated that DBA/2J mice exposed to the repeated-flurothyl model develop spontaneous seizures without evidence of seizure remission and provide a new model of epileptogenesis. Moreover, these findings indicated that the transition of forebrain ictal discharge into the brainstem seizure network occurs due to changes in brainstem seizure thresholds that are independent of spontaneous seizure expression.