Reeler homozygous mice exhibit enhanced susceptibility to epileptiform activity

Purpose: Seizures are observed frequently in humans with diffuse neuronal migration disorders. The reeler mutant mouse also exhibits a diffuse disruption of migration, yet no proepileptic phenotype has been reported for this model. Whether this disparity reflects a phenotypic difference that can be used to delineate the mechanisms associated with increasing seizure susceptibility or reflects a paucity of knowledge is unclear. Consequently, this study examined whether seizure susceptibility is altered in reeler mutant mice. Methods: In vivo (minimal electroshock delivered transcorneally) and in vitro techniques (field-potential recordings in neocortical and hippocampal brain slice preparations exposed to bicuculline methiodide) were used to determine whether the susceptibility to epileptiform activity is enhanced in reeler homozygous mice relative to controls. Adult (3-7 months) male reeler homozygotes (rl/rl) and controls (+/?) were identified based on their behavioral phenotype and were used in all experiments. Results: Minimal electroshock revealed that rl/rl mice, compared with controls, exhibited a lower threshold for electroshock-induced seizures (4.5 +/- 0.52 vs. 6.7 +/- 0.35 mA), and a higher incidence of behavioral seizures (median seizure score, class 4 vs. class 0) when animals were subjected to a 5-mA electroshock stimulus. Additionally, neocortical and hippocampal slices from rl/rl mice were more likely to generate spontaneous epileptiform activity after bicuculline application, compared with controls, and the duration of the epileptiform events elicited in 10-30 mu M bicuculline was longer in slices from rl/rl mice. Conclusions: These data demonstrate that rl/rl mice have enhanced seizure susceptibility that is in part intrinsic to the malformed neocortex and hippocampus. Thus in contrast to prior belief, most animal models of diffuse neuronal migration disorders do exhibit a proepileptic phenotype.