title: Anomalous inhibitory circuits in cortical tubers of human tuberous sclerosis complex associated with refractory epilepsy: aberrant expression of parvalbumin and calbindin-D28k in dysplastic cortex.
abstract: Damage or loss of inhibitory cortical gamma-aminobutyric acid (GABA)ergic interneurons is associated with impaired inhibitory control of neocortical pyramidal cells, leading to hyperexcitability and epileptogenesis. The calcium binding proteins parvalbumin and calbindin-D(28k) are expressed in subpopulations of GABAergic local circuit neurons in the neocortex and can serve as neuronotypic markers. Parvalbumin and calbindin-D(28k) facilitate the neuron's ability to sustain firing and provide neuroprotection. The goal of this study was to assess the hitherto unknown status of inhibitory interneurons in cortical tubers of human tuberous sclerosis complex. Surgically excised cortical tubers from three patients with tuberous sclerosis complex were evaluated immunohistochemically with antibodies to parvalbumin and calbindin-D(28k). Cortical specimens from young patients with intractable seizures, including microdysgenesis (n = 3), postischemic cortical scarring (n = 1), porencephaly (n = 1), postictal gliosis (n = 3), and low-grade neuronal or glial tumors (n = 5), were also examined for comparison. In cortical tubers, calcium binding protein immunoreactivities (calbindin-D(28k) > parvalbumin) were present in medium- or large-size dysplastic neurons, whereas giant or ballooned cells were parvalbumin or calbindin-D(28k) negative. In microdysgenesis, a nearly normal number of parvalbumin-positive neurons and a decreased number of calbindin-D(28k)-positive neurons were present. In peritumoral but more so in gliotic cortex, a coordinate decrease of parvalbumin and calbindin-D(28k) immunoreactivities was present. Our findings indicate that the expression of parvalbumin or calbindin-D(28k) by subpopulations of dysplastic neurons in cortical tubers is aberrant and denotes dysfunctional inhibitory circuits inept for excitoprotection.
authors.affiliation: Department of Pediatrics, Drexel University College of Medicine, Section of Neurology, St. Christopher's Hospital for Children, Philadelphia, PA, USA. Ignacio.Valencia@drexelmed.edu
authors.forename: Ignacio
authors.initials: I
authors.lastname: Valencia
authors.forename: Agustin
authors.initials: A
authors.lastname: Legido
authors.forename: Karina
authors.initials: K
authors.lastname: Yelin
authors.forename: Divya
authors.initials: D
authors.lastname: Khurana
authors.forename: Sanjeev V
authors.initials: SV
authors.lastname: Kothare
authors.forename: Christos D
authors.initials: CD
authors.lastname: Katsetos
mesh_terms: D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D064092:Calbindin 1; D064026:Calbindins; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000502:physiology*; D002540:Cerebral Cortex / Q000002:abnormalities / Q000473:pathology* / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D019610:Cytoprotection / Q000502:physiology; D003712:Dendrites / Q000378:metabolism / Q000473:pathology; D004827:Epilepsy / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology; D005911:Gliosis / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D007395:Interneurons / Q000378:metabolism / Q000473:pathology; D009433:Neural Inhibition / Q000502:physiology*; D009434:Neural Pathways / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D010320:Parvalbumins / Q000378:metabolism; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D014402:Tuberous Sclerosis / Q000150:complications / Q000473:pathology* / Q000503:physiopathology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D015415:Biomarkers; C576498:CALB1 protein, human; D064092:Calbindin 1; D064026:Calbindins; D002135:Calcium-Binding Proteins; D010320:Parvalbumins; D064030:S100 Calcium Binding Protein G; D005680:gamma-Aminobutyric Acid; D002118:Calcium