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

Abstract

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.

A companion to the preclinical common data elements for pharmacologic studies in animal models of seizures and epilepsy. A Report of the TASK3 Pharmacology Working Group of the ILAE/AES Joint Translational Task Force

“…For investigators wishing to evaluate investigational agents or pursue pharmacologic studies for specific patient populations, we encourage the implementation of these CRFs and CDEs with adjustments for the specific model at hand. Moreover, although every effort is made to be thorough in these model summaries and CDEs/CRFs, we understand that variability can arise because of region, diet, humidity, animal vendor, and so on, and can contribute to lab‐to‐lab variability . Thus, in all aspects of model implementation and development, we strongly encourage that the criteria for any model be independently reviewed and refined within each laboratory, using these CDE/CRFs to guide implementation.…”

“…Moreover, although every effort is made to be thorough in these model summaries and CDEs/CRFs, we understand that variability can arise because of region, diet, humidity, animal vendor, and so on, and can contribute to lab-to-lab variability. [12][13][14] Thus, in all aspects of model implementation and development, we strongly encourage that the criteria for any model be independently reviewed and refined within each laboratory, using these CDE/CRFs to guide implementation. This is to say, for example, if a median convulsant dose of pentylenetetrazol (PTZ) is needed by an individual lab, we suggest first evaluating the time and dose response to the desired endpoint in the animal strain of interest prior to selecting the PTZ dose and timing of administration.…”

Fenfluramine, a serotonin‐releasing drug, prevents seizure‐induced respiratory arrest and is anticonvulsant in the DBA/1 mouse model of SUDEP

“…8,9 High-intensity acoustic stimuli induce audiogenic seizures (Sz) in DBA/1 mice, which begin with wild running behavior and proceed to tonic seizures, which are followed by seizure-induced respiratory arrest (S-IRA) that results in death in the immediate postictal period. 8,9 High-intensity acoustic stimuli induce audiogenic seizures (Sz) in DBA/1 mice, which begin with wild running behavior and proceed to tonic seizures, which are followed by seizure-induced respiratory arrest (S-IRA) that results in death in the immediate postictal period.…”

“…DBA/1 mice are a chronically susceptible and reliable animal model of SUDEP that shows an inherited and abnormally high degree of seizure-induced death in response to electroconvulsive shock, hyperthermia, convulsant drug, and acoustic stimulation. 8,9 High-intensity acoustic stimuli induce audiogenic seizures (Sz) in DBA/1 mice, which begin with wild running behavior and proceed to tonic seizures, which are followed by seizure-induced respiratory arrest (S-IRA) that results in death in the immediate postictal period. Timely mechanical support of respiration can consistently reverse S-IRA in this SUDEP model.…”

Consequences of housing conditions and interindividual diversity in rodent models of acquired epilepsy

“…Heterogeneity in anxiety or cognitive performance at baseline in rodents and its potential consequence for subsequent induction of epilepsy, associated comorbidities, and drug response are not a new observation but have been known for decades. 17 For instance, Adamec et al 18,19 reported interindividual differences in the premorbid affective state of male Wistar rats that contributed to the behavioral effects of amygdala kindling. Their experiments suggested that premorbid anxiety state interacts with amygdala kindling to determine behavioral outcome, and that the outcome may be either anxiogenic, anxiolytic, or no effect at all depending on the level of anxiety at the time of kindling.…”