title: Evidence for mTOR pathway activation in a spectrum of epilepsy-associated pathologies.
abstract: BACKGROUND
  Activation of the mTOR pathway has been linked to the cytopathology and epileptogenicity of malformations, specifically Focal Cortical Dysplasia (FCD) and Tuberous Sclerosis (TSC). Experimental and clinical trials have shown than mTOR inhibitors have anti-epileptogenic effects in TS. Dysmorphic neurones and balloon cells are hallmarks of FCDIIb and TSC, but similar cells are also occasionally observed in other acquired epileptogenic pathologies, including hippocampal sclerosis (HS) and Rasmussen's encephalitis (RE). Our aim was to explore mTOR pathway activation in a range of epilepsy-associated pathologies and in lesion-negative cases.
  
  
  RESULTS
  50 epilepsy surgical pathologies were selected including HS ILAE type 1 with (5) and without dysmorphic neurones (4), FCDIIa (1), FCDIIb (5), FCDIIIa (5), FCDIIIb (3), FCDIIId (3), RE (5) and cortex adjacent to cavernoma (1). We also included pathology-negative epilepsy cases; temporal cortex (7), frontal cortex (2), paired frontal cortical samples with different ictal activity according to intracranial EEG recordings (4), cortex with acute injuries from electrode tracks (5) and additionally non-epilepsy surgical controls (3). Immunohistochemistry for phospho-S6 (pS6) ser240/244 and ser235/236 and double-labelling for Iba1, neurofilament, GFAP, GFAPdelta, doublecortin, and nestin were performed. Predominant neuronal labelling was observed with pS6 ser240/244 and glial labelling with pS6 ser235/236 in all pathology types but with evidence for co-expression in a proportion of cells in all pathologies. Intense labelling of dysmorphic neurones and balloon cells was observed in FCDIIb, but dysmorphic neurones were also labelled in RE and HS. There was no difference in pS6 labelling in paired samples according to ictal activity. Double-labelling immunofluorescent studies further demonstrated the co-localisation of pS6 with nestin, doublecortin, GFAPdelta in populations of small, immature neuroglial cells in a range of epilepsy pathologies.
  
  
  CONCLUSIONS
  Although mTOR activation has been more studied in the FCDIIb and TSC, our observations suggest this pathway is activated in a variety of epilepsy-associated pathologies, and in varied cell types including dysmorphic neurones, microglia and immature cell types. There was no definite evidence from our studies to suggest that pS6 expression is directly related to disease activity.
authors.forename: Joan
authors.initials: J
authors.lastname: Liu
authors.forename: Cheryl
authors.initials: C
authors.lastname: Reeves
authors.forename: Zuzanna
authors.initials: Z
authors.lastname: Michalak
authors.forename: Antonietta
authors.initials: A
authors.lastname: Coppola
authors.forename: Beate
authors.initials: B
authors.lastname: Diehl
authors.forename: Sanjay M
authors.initials: SM
authors.lastname: Sisodiya
authors.affiliation: Departments of Neuropathology, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK. m.thom@ucl.ac.uk.
authors.forename: Maria
authors.initials: M
authors.lastname: Thom
mesh_terms: D000293:Adolescent; D000328:Adult; D015703:Antigens, CD / Q000378:metabolism; D002135:Calcium-Binding Proteins; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D002648:Child; D004268:DNA-Binding Proteins / Q000378:metabolism; D000089622:Doublecortin Domain Proteins; D004827:Epilepsy / Q000209:etiology / Q000473:pathology*; D005260:Female; D006801:Humans; D007382:Intermediate Filaments / Q000378:metabolism; D008297:Male; D054220:Malformations of Cortical Development / Q000150:complications; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008875:Middle Aged; D009479:Neuropeptides / Q000378:metabolism; D038601:Ribosomal Protein S6 / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014402:Tuberous Sclerosis / Q000150:complications; D055815:Young Adult
chemical_list: C112986:AIF1 protein, human; D015703:Antigens, CD; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D000089622:Doublecortin Domain Proteins; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D038601:Ribosomal Protein S6; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases