title: Prenatal freeze lesioning produces epileptogenic focal cortical dysplasia.
abstract: OBJECTIVE
  Focal cortical dysplasia (FCD) is thought to be 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 verify whether FCD influences seizure activities.
  
  
  METHODS
  At 18 days postconception, a frozen probe was placed on the left scalp of a Sprague-Dawley rat embryo through the uterus wall. 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.
  
  
  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 42.1% of cases. ADs in the 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 and spontaneous cortico-hippocampal spikes, even in the chronic EEG recordings. Immunoreactivities for N-methyl-D-aspartate receptor (NMDAR) subunit 2B and glutamate/aspartate transporter in the lesions were significantly enhanced compared with the nonlesioned 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 is associated with vulnerability to epilepsy, and may augment hippocampal epileptogenicity.
authors.affiliation: Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Kei-ichiro
authors.initials: K
authors.lastname: Takase
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shigeto
authors.forename: Satoshi O
authors.initials: SO
authors.lastname: Suzuki
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kikuchi
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Ohyagi
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Kira
mesh_terms: D027322:Amino Acid Transport System X-AG / Q000032:analysis; D000818:Animals; D004195:Disease Models, Animal; D004292:Dominance, Cerebral / Q000502:physiology; D004569:Electroencephalography; D017034:Epilepsy, Frontal Lobe / Q000473:pathology / Q000503:physiopathology*; D004830:Epilepsy, Tonic-Clonic / Q000473:pathology / Q000503:physiopathology; D005071:Evoked Potentials / Q000502:physiology; D005260:Female; D005615:Freezing; D005865:Gestational Age; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology; D007696:Kindling, Neurologic / Q000502:physiology; D008297:Male; D054220:Malformations of Cortical Development / Q000473:pathology / Q000503:physiopathology*; D008869:Microtubule-Associated Proteins / Q000032:analysis; D011247:Pregnancy; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000032:analysis
chemical_list: D027322:Amino Acid Transport System X-AG; D005904:Glial Fibrillary Acidic Protein; D008869:Microtubule-Associated Proteins; C120997:NR2A NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate