DECREASED BRAIN-STEM SEIZURE THRESHOLDS AND FACILITATED SEIZURE PROPAGATION IN MICE EXPOSED TO REPEATED FLUROTHYL-INDUCED GENERALIZED FOREBRAIN SEIZURES

We recently have described a novel model of epileptogenesis utilizing the inhalant chemoconvulsant, flurothyl (Applegate et al., 1997; Samor iski and Applegate, 1997). The hallmark feature of this model is a cha nge in behavioral seizure phenotype fi om a forebrain seizure, observe d during the initial flurothyl exposures, to a brainstem seizure, elic ited by flurothyl, after a 28-day stimulation free incubation period. In this study, we sought to establish the basis for this change in beh avioral seizure response. To this end, we examined the effects of expo sure to this paradigm on the generalized brainstem seizure threshold a nd on the propagation of forebrain seizures onto the brainstem seizure substrate. Ten mice were given flurothyl-induced generalized forebrai n seizures on 8 consecutive days (induction phase). The other ten mice were not exposed to the flurothyl induction paradigm and served as co ntrols. Minimal corneal electroconvulsive shock (mECS-20 mA) was used to assay whether there was any change in the animals' generalized brai nstem seizure thresholds at 3, 14 and 28 days following the last fluro thyl seizure trial. Mice that were exposed to flurothyl exhibited a pr ogressive increase in the percentage of animals having a mECS-induced brainstem seizure when tested at 3 (40%), 14 (70%) and 28 (90%) days f ollowing the last flurothyl seizure. Control mice rarely had a brainst em seizure at any of the three time points tested, mostly forebrain se izures were observed. These results suggest that there is a significan t progressive lowering of the brainstem seizure threshold, during the incubation phase of the flurothyl paradigm, which is coincident with t he previously reported time course of change in the behavioral seizure phenotype observed using this flurothyl model (Applegate et al., 1997 ; Samoriski and Applegate, 1997). Following mECS testing, mice were im planted with bipolar electrodes and kindled from the olfactory bulb (O B). Mice exposed to the flurothyl paradigm demonstrated significantly faster kindling rates, longer afterdischarge durations, and longer dur ations of and latencies to stage 5 seizures compared to controls. Furt hermore, animals exposed to the flurothyl protocol demonstrated an inc rease in the expression of brainstem seizures after focally-elicited O B afterdischarges. These results suggest that there is an increased in teraction between the forebrain and brainstem seizure systems after ex posure to this model of epileptogenesis. Together, results indicate th at the change in behavioral seizure phenotype observed following expos ure to our flurothyl paradigm are promoted by both decreases in brains tem seizure thresholds and facilitated forebrain seizure propagation o nto the brainstem seizure system. (C) 1998 Elsevier Science B.V. All r ights reserved.