Differential Susceptibility to Seizures Induced by Systemic Kainic Acid Treatment in Mature DBA/2J and C57BLl6J Mice

Abstract

Mature DBA/2J (D2) and C57BL/6J (B6) mice aged 9-10 weeks were studied to determine susceptibility to behavioral seizures induced by kainic acid (KA) and the possible influence exerted by differences in metabolism and blood-brain barrier (BBB) transport. Mice were observed for 4 h after subcutaneous (s.c.) KA injection. Behavioral seizure parameters included latency to first seizure (clonus), latency to tonic/clonic seizure, and latency to status epilepticus (SE). At a KA dose of 25 mg/kg, 80% of D2 mice exhibited tonic/clonic seizures, whereas all B6 mice remained seizure-free. At 30 mg/kg, tonic/clonic seizures were observed in 100% of D2 mice and 25% of B6 mice. Of D2 mice exhibiting at least one clonic seizure in response to KA at a dose of 25 mg/kg, 50% entered SE and eventually died. Administration of [3H]KA (6.6 x 10(6) dpm) at doses of 25 mg/kg (convulsive) or 11.1 micrograms (nonconvulsive) to mice of both strains resulted in similar levels of radioactivity in cortex, hippocampus, and cerebellum 30 and 60 min after injection. Bioconversion of [3H]KA to a radiolabeled brain metabolite in vivo could not be documented in mice from either strain. Results confirm previously reported differences between D2 and B6 mice in their relative susceptibility to seizures induced by systemic KA administration and suggest that these differences are not related to strain-specific variation in metabolism or BBB transport of KA. Further studies of these two strains of mice may be useful for investigating genetic influences upon seizure susceptibility.

Acute Cocaine-Induced Seizures Differential Sensitivity of Six Inbred Mouse Strains

“…C57 mice were never observed to exhibit abnormal electrical discharges characteristic of seizure activity whereas behavioral seizure activity in SJL and A/J was always associated with EEG spiking. These results are consistent with a large body of literature documenting that C57 mice are unique in their relatively high degree of resistance to many types of experimental seizures (Schlesinger et al 1968;Deckard et al 1976;Kellogg 1976;Engstrom and Woodbury 1988;Kosobud and Crabbe 1990;Ferraro et al 1995aFerraro et al , 1998. The study by Marley (Marley et al 1991a) relied solely upon behavioral observation for evaluation of seizure activity and it is possible that motor dysfunction such as ataxia or other involuntary movements, which we observed in cocaine-treated C57 mice, were scored as seizures.…”

“…Confirming several literature reports for sensitivity to KA seizures (Engstrom and Woodbury 1988;Ferraro et al 1995aFerraro et al , 1997, results showed that DBA mice were most sensitive whereas C57 mice were most resistant. A/J mice were more like C57 whereas SJL mice were more like DBA.…”

“…In order to evaluate the possibility that susceptibility to cocaine may be a more general phenomenon related to overall seizure predisposition rather than to a specific action of cocaine, strain sensitivities to kainic acid (KA) induced seizures were compared with sensitivities to cocaine-induced seizures. Confirming several literature reports for sensitivity to KA seizures (Engstrom and Woodbury 1988;Ferraro et al 1995aFerraro et al , 1997, results showed that DBA mice were most sensitive whereas C57 mice were most resistant. A/J mice were more like C57 whereas SJL mice were more like DBA.…”

“…Behavior was monitored for 20 minutes after the administration of cocaine. Latency to onset of behavioral seizure activity and number and type of behavioral seizures during the 20-min observation period were recorded by two observers with inter-rater reliability established in previous studies on kainate-induced seizure phenotypes in these and other strains (Golden et al 1991(Golden et al , 1994(Golden et al , 1995Ferraro et al 1995aFerraro et al , 1995bFerraro et al , 1997. In contrast to other pharmacological seizure inducing agents, cocaine typically produces a much sharper transition from non-convulsive behavior to generalized convulsions with little indication of intermediate forms such as myoclonic jerks.…”

Use of chromosome substitution strains to identify seizure susceptibility loci in mice

“…Inbred mouse strains differ in susceptibility to developing seizures in response to toxic, electrical, and auditory insults to the nervous system, and these differences are heritable (Fehr et al 2002;Ferraro et al 1995Ferraro et al , 1997Ferraro et al , 1998 Collins 1991, 1992). Heritability has been demonstrated by breeding studies in which offspring of parental crosses develop intermediate phenotypes, and loci underlying strain differences in susceptibility have been identified using QTL mapping in these models (Table 1).…”