Abstracts

Rationale: Focal cortical dysplasia (FCD) is an important cause of intractable epilepsy. Because neonatal freeze lesion rat models do not show spontaneous seizures without seizure-provoking events, we created a rat model with multiple FCD, produced during embryonic development, and revealed that some of them have spontaneous seizures arising from the hippocampus. In this study, we generated more rats with prenatal freeze lesions to confirm the occurrence of spontaneous seizure. Furthermore, we examined the relationship between FCD and epileptogenesis using an immunohistochemical procedure to investigate the mechanism underlying epilepsy with FCD. Methods: At 18 days postconception, a frozen metal probe was placed bilaterally on the scalps of Sprague-Dawley rat embryos through the uterus wall to produce multiple FCD. Rats were divided into groups receiving bilateral lesions with two lesions in each hemisphere (bilateral multiple lesion rats), bilateral lesions with a single lesion in each hemisphere (bilateral single lesion rats), and bilateral sham operations (bilateral sham-operated rats). EEG was performed intermittently from postnatal day 35 to postnatal day 77 in the bilateral frontal cortices and hippocampi. Video recording was used to monitor behavior. Brain tissues were examined immunohistochemically at postnatal days 28 and 78 using semiquantitative densitometry. Results: Eleven of 16 bilateral multiple lesion rats (68.8%) showed spontaneous electroencephalographic hippocampal seizures from postnatal day 47. No seizures were observed in bilateral single lesion or sham-operated animals. Movement cessation followed by sniffing and mastication, culminating in wet-dog shaking, was seen during the hippocampal discharges. FCD was observed in the bilateral frontoparietal lobes. Although spontaneous seizures were not seen at FCD lesions, the expression levels of N-methyl-D-aspartate receptor (NMDAR) subunits 1, 2A, 2B, the glutamate/aspartate transporter and the glial glutamate transporter 1 at FCD lesions were increased at postnatal days 28 and 78. There were no major histological abnormalities in the hippocampi compared with those in the cortex. However, the expression levels of N-methyl-D-aspartate receptor (NMDAR) subunits 2A and 2B were increased in the hippocampi at postnatal day 28. Also, levels of NMDAR1, 2A and 2B, the glutamate/aspartate transporter and the glial glutamate transporter 1 were increased in the hippocampi at postnatal day 78. Conclusions: We confirmed the reproducibility of spontaneous temporal lobe seizures in a rat model with multiple FCD produced during embryonic development. Increased excitability via glutamatergic receptors was observed both in FCD lesions and the hippocampus. This model should help clarify the mechanisms underlying temporal lobe epilepsy.