Genetic and phenotypic analysis of seizure susceptibility in PL/J mice

Abstract

Epilepsy is one of the most common but genetically complex neurological disorders in humans. Identifying animal models that recapitulate human epilepsies is important for pharmacological studies of anticonvulsants, dissection of molecular and biochemical pathogenesis of epilepsy, and discovery of epilepsy susceptibility genes. We discovered that the PL/J inbred mouse strain is susceptible to handling- and rhythmic tossing-induced seizure. The tonic-clonic and generalized seizures observed after induction were accompanied by abnormal EEGs, similar to seizures observed in EL and SWXL-4 mice. PL/J mice also had an extremely low threshold to electroconvulsive seizures compared to other strains and showed variable sensitivity to pentylenetetrazole-induced seizures. Gross neurostructural abnormalities were not found in PL/J mice. Crosses with the seizure-resistant C57BL/6 J strain revealed semidominant inheritance of the rhythmic tossing seizure trait with low penetrance. F2 progeny indicated that the genetic inheritance of seizure susceptibility in PL/J is non-Mendelian. We crossed DBA/2 J mice, which are resistant to rhythmic tossing seizure but susceptible to audiogenic seizures, to PL/J. We found that seizure penetrance in (DBA/2 J x PL/J)F1 mice was similar to the penetrance in (C57BL/6 J x PL/J)F1 mice but the severity and frequency of seizure were higher in (DBA/2 J x PL/J)F1 mice. The PL/J strain serves as an interesting new model for studying the genetics, neurobiology, and pharmacology of epilepsy.

Social approach and repetitive behavior in eleven inbred mouse strains

“…In the present study, C58/ J, PL/J, and SWR/J all demonstrated poor learning during the initial phase of the T-maze task. The low performance in the PL/J strain may have been due, in part, to the seizure-like responses characteristic of this strain [21]. So far, only one strain, SJL/J, has shown rapid acquisition of the task, without meeting criterion for learning during reversal.…”

“…By the end of the study, a distinctive, persistent back-flipping behavior was observed in all 5 home cages of C58/J mice (with 4 mice per cage). Observations of another strain, PL/J, indicated that 30% of the mice had seizurelike responses during the social approach tests (see [21]). …”

Seizure logging: A new approach to synchronized cable-free EEG and video recordings of seizure activity in mice

“…Such cable-based systems hardly impose problems for studies of seizures that rely on electrical or chemical induction. However, in many epilepsy models, the most studied being the El mouse, seizures appear during complex stimulus situations such as daily handling procedures (Etholm and Heggelund, 2009;Kitami et al, 2004;Todorova et al, 1999). In such studies cable-based systems cause problems because one would try to mimic situations where seizures are normally seen.…”

“…Problems with evoking seizures during EEG-recording can be bypassed by using pharmacological agents (Nakano et al, 1994), but this may seriously change the nature of the seizure studied. The risk of changing the phenomenon studied is also present in cases where the stimulus intensity is increased by for instance replacing simple cage changing procedures with more traditional tossing procedures (Imaizumi et al, 1959), or where one is changing such tossing regimes to make them practical with cable-tethered animals (Etholm and Heggelund, 2009;Kitami et al, 2004;Suzuki and Nakamoto, 1977). Moreover, such elaborate movement regimes (Imaizumi et al, 1959) can induce large movement artifacts, especially during the initial parts of the seizures that are often of great interest.…”

Development of a New Genetic Model for Absence Epilepsy: Spike-Wave Seizures in C3H/He and Backcross Mice

“…Many mouse strains (including C3H) carry a mutation in the Pde6b gene that causes severe retinal generation (Pittler and Baehr, 1991); others (such as I/Ln) carry mutations such as piebald with defects in the development of the neural crest; these are just two of many examples (Bogue, 2003). In the field of epilepsy, several mouse strains (e.g., EL, SWXL-4, PL) exhibit tonic-clonic and generalized convulsions with routine handling (Rise et al, 1991;Frankel et al, 1994;Kitami et al, 2004). In some strains, it has been shown that convulsions are explained by the inheritance of susceptibility alleles from nonepileptic parental strains (Frankel et al, 1994).…”