Focal epileptogenesis in a rat model of polymicrogyria

Polymicrogyria, a developmental cortical malformation associated with epile psy, can be modeled in rats with a transcortical freeze lesion on the day o f birth (P0) or P1. We have used field potential recordings to characterize the incidence, propagation patterns, and distribution of epileptiform acti vity in slices from rats with experimental microgyri. Interictal-like epile ptiform activity was evoked in slices from 85% of freeze-lesioned rats aged P12-P118. These data show age-specific properties of epileptogenesis, incl uding: a delay in onset, a decrease in the incidence of epileptiform activi ty in rats >P40 that was specific to those lesioned on P0 as opposed to P1, and a shift in the likely site of initiation to areas further from the mic rogyrus in mature animals. Several observations suggest that the area adjac ent to the microgyrus, which appears histologically normal in Nissl stains, contains the necessary epileptogenic neuronal circuits: 1) in 78% of slice s, epileptiform activity could be evoked only from a focal zone adjacent to the microgyrus (paramicrogyral zone) and not within the microgyrus proper; 2) epileptiform activity consistently originated from a particular site wi thin this paramicrogyral zone, independent of the location of the stimulati ng electrode, suggesting that the generator is outside of the microgyrus; 3 ) evoked epileptiform activities in the paramicrogyral cortex were unaltere d after separation of this zone from the microgyrus with a transcortical cu t; and 4) the short-latency graded field potential evoked in the paramicrog yral zone contained an additional negativity not seen in control slices. Th e epileptiform activity was blocked reversibly by N-methyl-D-aspartate rece ptor antagonists in slices from mature as well as immature freeze-lesioned rats. These results suggest that aberrant synaptic connectivity develops in rat cortex surrounding the microgyrus and produces a focal epileptogenic z one whose capacity to generate epileptiform activities does not depend on c onnections with the malformation itself. We hypothesize that afferents, ori ginating from cortical and extracortical sites, lose their targets in the r egion of the malformation and make appropriate laminar contacts in the cort ex adjacent to the malformation, creating an overabundance of excitatory in put to this cortical zone. increased excitatory feedback onto specific cort ical elements may be one factor involved in epileptogenesis in this model o f a cortical malformation.