title: FCD Type II and mTOR pathway: Evidence for different mechanisms involved in the pathogenesis of dysmorphic neurons.
abstract: Type II focal cortical dysplasia (FCD II) is a malformation of cortical development, frequently associated with intractable epilepsy, characterised by cortical dyslamination, dysmorphic neurons (DNs) and balloon cells (BCs). We investigated the expression of pS6 (downstream target) and pPDK1-pAkt (upstream targets) as evidence for mTOR pathway activation and their co-expression with Interleukin-1β in FCD II surgical specimens and compared the findings with control non-epileptic tissue, non-malformed epileptic tissue or acquired epilepsy-Rasmussen's Encephalitis (RE) occasionally presenting pS6 and Interleukin-1β positive abnormal neurons. Downstream mTOR activation was demonstrated in almost all abnormal cells in both FCD II and RE. Conversely, upstream activation in FCD II was observed in the majority of BCs, in a proportion of DNs, not presenting Interleukin-1β expression, but not at all in RE scattered abnormal neurons. Based on these findings we suggest that the presence of BCs and DNs in FCD II could be due to a first upstream mTOR pathway PI3K-Akt-mediate event occurring very early during cortical development in the large proportion of abnormal cells; followed by the appearance of additional pS6 positive DNs promoted by the presence of a later inflammatory processes.
authors.affiliation: Clinical Epileptology and Experimental Neurophysiology Unit, Fondazione IRCCS, Istituto Neurologico "C. Besta", Milan, Italy. Electronic address: laura.rossini@istituto-besta.it.
authors.forename: Laura
authors.initials: L
authors.lastname: Rossini
authors.affiliation: Clinical Epileptology and Experimental Neurophysiology Unit, Fondazione IRCCS, Istituto Neurologico "C. Besta", Milan, Italy.
authors.forename: Flavio
authors.initials: F
authors.lastname: Villani
authors.affiliation: Department of Pediatric Neuroscience, Fondazione IRCCS, Istituto Neurologico "C. Besta", Milan, Italy.
authors.forename: Tiziana
authors.initials: T
authors.lastname: Granata
authors.affiliation: Epilepsy Surgery Centre "C. Munari", Ospedale Niguarda, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Tassi
authors.affiliation: Neurosurgery Unit, Fondazione IRCCS, Istituto Neurologico "C. Besta", Milan, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tringali
authors.affiliation: Epilepsy Surgery Centre "C. Munari", Ospedale Niguarda, Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cardinale
authors.affiliation: Department of (Neuro)Pathology, Academic Medical Center and Swammerdam Institute for Life Sciences, Center for Neuroscience University of Amsterdam; Stichting Epilepsie Instellingen Nederland (SEIN), The Netherlands.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Aronica
authors.affiliation: Clinical Epileptology and Experimental Neurophysiology Unit, Fondazione IRCCS, Istituto Neurologico "C. Besta", Milan, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Spreafico
authors.affiliation: Clinical Epileptology and Experimental Neurophysiology Unit, Fondazione IRCCS, Istituto Neurologico "C. Besta", Milan, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Garbelli
mesh_terms: D000293:Adolescent; D000328:Adult; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D002648:Child; D002675:Child, Preschool; D000069279:Drug Resistant Epilepsy / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D004827:Epilepsy / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D065703:Malformations of Cortical Development, Group I / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D055815:Young Adult
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human
keywords: Epilepsy surgery; Focal cortical dysplasia; inflammation; mTOR pathway; pI3K-Akt pathway; pS6