Abstracts

Rationale: Focal cortical dysplasia (FCD) is thought to an important cause of intractable epilepsy. However, its epileptogenicity remains unclear. Therefore, we created a novel rat model by freeze lesioning during the late embryonic stage to investigate the epileptogenicity of extratemporal FCD and to explain the relationship between extratemporal FCD and development of hippocampal kindling. Methods: At 18 days post-conception, a frozen probe was placed on the left frontal scalp of a Sprague-Dawley rat embryo through the uterus wall. Rat pups were classified as freeze-lesioned (n=19), sham-operated (n=7) and control rats (n=19). Freeze-lesioned and control rats were also subdivided into electrical stimulated until P77 (n=7), never electrical stimulated until P77 (n=7) and sacrificed animals at P28 without any electrical stimulation (n=5). For 40 consecutive days from postnatal day 38 (P38), electrical kindling stimulation was applied to the frontal lobes of male rat pups. Afterdischarges (ADs) were measured in both the cortex and hippocampus. Brain tissues were examined by immunohistochemistry, including semi-quantitative densitometry. Results: All brains from prenatally freeze-lesioned rats displayed severe disorganization of the cortical layers with randomly oriented dendrites/axons. In addition, heterotopic cortices were observed in 41.2% of cases. ADs in the frontal cortex and hippocampus were significantly prolonged in freeze-lesioned rats compared with those in sham-operated and control rats. FCD rats also revealed early development of hippocampal kindling. They also showed spontaneous cortico-hippocampal spikes even in the chronic EEG recording. Immunoreactivities for N-methyl-D-aspartate receptor (NMDAR) subunit 2B and glutamate/aspartate transporter in the lesions were significantly enhanced compared with the non-lesioned side, even in the absence of electrical stimulation. After electrical stimulation, NMDAR1 and 2B were markedly upregulated not only in the FCD but also in the hippocampus. Conclusions: Prenatal freeze lesioning of the brain produces a severe neuronal migration disorder, closely mimicking human FCD. Our model suggests that FCD has vulnerability to epilepsy and may augment hippocampal epileptogenicity.