title: Convulsive seizures from experimental focal cortical dysplasia occur independently of cell misplacement.
abstract: Focal cortical dysplasia (FCD), a local malformation of cortical development, is the most common cause of pharmacoresistant epilepsy associated with life-long neurocognitive impairments. It remains unclear whether neuronal misplacement is required for seizure activity. Here we show that dyslamination and white matter heterotopia are not necessary for seizure generation in a murine model of type II FCDs. These experimental FCDs generated by increasing mTOR activity in layer 2/3 neurons of the medial prefrontal cortex are associated with tonic-clonic seizures and a normal survival rate. Preventing all FCD-related defects, including neuronal misplacement and dysmorphogenesis, with rapamycin treatments from birth eliminates seizures, but seizures recur after rapamycin withdrawal. In addition, bypassing neuronal misplacement and heterotopia using inducible vectors do not prevent seizure occurrence. Collectively, data obtained using our new experimental FCD-associated epilepsy suggest that life-long treatment to reduce neuronal dysmorphogenesis is required to suppress seizures in individuals with FCD.
authors.affiliation: Departments of Neurosurgery, and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520-8082, USA.
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Hsieh
authors.affiliation: Departments of Neurosurgery, and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520-8082, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Wen
authors.affiliation: Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06520-8082, USA.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Claycomb
authors.affiliation: Magnetic Resonance Research Center, Yale University School of Medicine, New Haven, Connecticut 06520-8082, USA.
authors.forename: Yuegao
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Biology, Wesleyan University, Middletown, Connecticut 06459, USA.
authors.forename: Felicia A
authors.initials: FA
authors.lastname: Harrsch
authors.affiliation: Department of Biology, Wesleyan University, Middletown, Connecticut 06459, USA.
authors.forename: Janice R
authors.initials: JR
authors.lastname: Naegele
authors.affiliation: Magnetic Resonance Research Center, Yale University School of Medicine, New Haven, Connecticut 06520-8082, USA.
authors.forename: Fahmeed
authors.initials: F
authors.lastname: Hyder
authors.affiliation: Department of Neurology, Yale University School of Medicine, New Haven, Connecticut 06520-8082, USA.
authors.forename: Gordon F
authors.initials: GF
authors.lastname: Buchanan
authors.affiliation: Departments of Neurosurgery, and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06520-8082, USA.
authors.forename: Angelique
authors.initials: A
authors.lastname: Bordey
mesh_terms: D000818:Animals; D002465:Cell Movement; D060825:Cognitive Dysfunction / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D054220:Malformations of Cortical Development / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012640:Seizures / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D066127:White Matter / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D049452:Green Fluorescent Proteins; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus