title: Characterization of focal cortical dysplasia with balloon cells by layer-specific markers: Evidence for differential vulnerability of interneurons.
abstract: Focal cortical dysplasia (FCD) is a major cause of pharmacoresistant focal epilepsy. Little is known about the pathomechanisms underlying the characteristic cytoarchitectural abnormalities associated with FCD. In the present study, a broad panel of markers identifying layer-specific neuron subpopulations was applied to characterize dyslamination and structural alterations in FCD with balloon cells (FCD 2b).
  
  
  
  Pan-neuronal neuronal nuclei (NeuN) and layer-specific protein expression (Reelin, Calbindin, Calretinin, SMI32 (nonphosphorylated neurofilament H), Parvalbumin, transducin-like enhancer protein 4 (TLE4), and Vimentin) was studied by immunohistochemistry on paraffin sections of FCD2b cases (n = 22) and was compared to two control groups with (n = 7) or without epilepsy (n = 4 postmortem cases). Total and layer-specific neuron densities were systematically quantified by cell counting considering age at surgery and brain region.
  
  
  
  We show that in FCD2b total neuron densities across all six cortical layers were not significantly different from controls. In addition, we present evidence that a basic laminar arrangement of layer-specific neuron subtypes was preserved despite the severe disturbance of cortical structure. SMI32-positive pyramidal neurons showed no significant difference in total numbers, but a reduction in layers III and V. The densities of supragranular Calbindin- and Calretinin-positive interneurons in layers II and III were not different from controls, whereas Parvalbumin-expressing interneurons, primarily located in layer IV, were significantly reduced in numbers when compared to control cases without epilepsy. In layer VI, the density of TLE4-positive projection neurons was significantly increased. Altogether, these data show that changes in cellular composition mainly affect deep cortical layers in FCD2b.
  
  
  
  The application of a broad panel of markers defining layer-specific neuronal subpopulations revealed that in FCD2b neuronal diversity and a basic laminar arrangement are maintained despite the severe disturbance of cytoarchitecture. Moreover, it showed that Parvalbumin-positive, inhibitory interneurons are highly vulnerable in contrast to other interneuron subtypes, possibly related to the epileptic condition.
authors.affiliation: Experimental Epilepsy Research, Department of Neurosurgery, Medical Center-University of Freiburg, Freiburg, Germany.|Department of Neurosurgery, Medical Center-University of Freiburg, Freiburg, Germany.|Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Julia M
authors.initials: JM
authors.lastname: Nakagawa
authors.affiliation: Experimental Epilepsy Research, Department of Neurosurgery, Medical Center-University of Freiburg, Freiburg, Germany.|Faculty of Medicine, University of Freiburg, Freiburg, Germany.|Faculty of Biology, University of Freiburg, Freiburg, Germany.
authors.forename: Catharina
authors.initials: C
authors.lastname: Donkels
authors.affiliation: Epilepsy Center Bethel, Bielefeld, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Fauser
authors.affiliation: Faculty of Medicine, University of Freiburg, Freiburg, Germany.|Epilepsy Center, Medical Center-University of Freiburg, Freiburg, Germany.|BrainLinks-BrainTools, Cluster of Excellence, University of Freiburg, Freiburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schulze-Bonhage
authors.affiliation: Faculty of Medicine, University of Freiburg, Freiburg, Germany.|Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.|BIOSS, Center for Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Prinz
authors.affiliation: Department of Neurosurgery, Medical Center-University of Freiburg, Freiburg, Germany.|Faculty of Medicine, University of Freiburg, Freiburg, Germany.
authors.forename: Josef
authors.initials: J
authors.lastname: Zentner
authors.affiliation: Experimental Epilepsy Research, Department of Neurosurgery, Medical Center-University of Freiburg, Freiburg, Germany.|Faculty of Medicine, University of Freiburg, Freiburg, Germany.|BrainLinks-BrainTools, Cluster of Excellence, University of Freiburg, Freiburg, Germany.
authors.forename: Carola A
authors.initials: CA
authors.lastname: Haas
mesh_terms: D000293:Adolescent; D000328:Adult; D064032:Calbindin 2 / Q000378:metabolism; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D002452:Cell Count; D002648:Child; D002675:Child, Preschool; D004827:Epilepsy / Q000473:pathology*; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D006801:Humans; D007223:Infant; D007395:Interneurons / Q000145:classification* / Q000378:metabolism*; D008297:Male; D065703:Malformations of Cortical Development, Group I / Q000473:pathology*; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism; D010320:Parvalbumins / Q000378:metabolism; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000378:metabolism; D018709:Statistics, Nonparametric; D055815:Young Adult
chemical_list: D064032:Calbindin 2; D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; D010320:Parvalbumins; D000091042:Reelin Protein; C051774:neurofilament protein H; C000717127:RELN protein, human; D012697:Serine Endopeptidases; D010751:Phosphopyruvate Hydratase
keywords: Epilepsy; Lamination; Malformation; Neocortical brain development; Parvalbumin