Abstracts

Cortical malformations are frequently associated with epilepsy, cognitive impairment and other neurological disorders. Reeler homozygous mice (rl/rl) are a model of cortical malformation that exhibit anatomical and genetic alterations similar to that observed in humans with lissencephaly with cerebellar hypoplasia. However, it is currently unclear whether seizure susceptibility/severity is altered in rl/rl mice. In vivo (minimal electroshock) and in vitro techniques (extracellular field potential recordings in hippocampal and neocortical brain slice preparations exposed to bicuculline methiodide) were used to assess whether the susceptibility to generate epileptiform activity or the severity of the epileptiform activity elicited is enhanced in rl/rl mice relative to controls. Males (2-4 months) were used in all experiments. In hippocampal slices, recordings were performed in the dentate gyrus (recording at the granule cell - molecular layer border), and in CA1 (both the superficial and deep layers of CA1 were examined in rl/rl mice). Additionally, since rl/rl mice exhibit an inverted lamination in the neocortex and only 4 primary layers, recordings were made in the deep layers from rl/rl mice and the superficial layers from controls. Minimal electroshock was delivered transcorneally using a Whalquist electroshock instrument (5 mA intensity; 60 Hz; 200 ms duration) and seizures were scored using a modified Racine[apos]s scale. Minimal electroshock elicited seizures [ge] class 3 in severity in 100% of rl/rl mice (n = 4), and in only 25% of controls (n=4). Following application of 30 [mu]m bicuculline, an increased probability of eliciting spontaneous prolonged negative field potential shifts (i.e. epileptiform activity) was observed in hippocampal slices from rl/rl mice relative to controls. Prolonged field potential shifts were observed in the dentate gyrus in 100% of slices from rl/rl mice and 0% from controls (25/25 vs 0/27 slices respectively). A similar increase in the probability of generating prolonged field potential shifts was observed in CA1 of rl/rl slices relative to controls (10/10 vs 4/10 slices, respectively). Furthermore, in 10 [mu]m bicuculline, neocortical slices from rl/rl mice exhibited epileptiform events that were of longer duration than those recorded in controls (rl/rl: duration = 5.1 [plusmn] 0.7 s, n = 4; control: duration = 3.4 [plusmn] 0.4 s, n=4). Both in vivo and in vitro data indicate that rl/rl mice exhibit an enhanced susceptibility/severity to epileptiform activity. Although additional experiments are needed, these data suggest that the rl/rl mouse may be a suitable model for examining how global and naturally occurring (in comparison with injury induced) cortical malformations contribute to a change in seizure susceptibility/severity. (Supported by ORDA grant SIUC)