title: Redistribution of PDGFRβ cells and NG2DsRed pericytes at the cerebrovasculature after status epilepticus.
abstract: OBJECTIVE
  The role of cerebrovascular dysfunction in seizure disorders is recognized. Blood-brain barrier (BBB) damage in epilepsy has been linked to endothelial and glial pathophysiological changes. Little is known about the involvement of pericytes, a cell type that contributes to BBB function.
  
  
  METHODS
  NG2DsRed mice were used to visualize cerebrovascular pericytes. The pattern of vascular and parenchymal distributions of platelet-derived growth factor receptor beta (PDGFRβ) cells was evaluated by immunohistochemistry. Status epilepticus was induced in NG2DsRed or C57BL/6J mice by intraperitoneal kainic acid (KA). Animals were perfused intracardially using FITC-Dextran or FITC-Albumin to visualize the cerebrovasculature. Colocalization was performed between NG2DsRed, PDGFRβ and microglia IBA-1. Confocal 3D vessel reconstruction was used to visualize changes in cell morphology and position. PDGFRβ expression was also evaluated in vitro using organotypic hippocampal cultures (OHC) treated with kainic acid to induce seizure-like activity. Co-localization of PDGFRβ with the vascular marker RECA-1 and NG2 was performed. Finally, we assessed the expression of PDGFRβ in brain specimens obtained from a cohort of patients affected by drug resistant epilepsy compared to available autoptic brain.
  
  
  RESULTS
  In vivo, severe status epilepticus (SE) altered NG2DsRed vascular coverage. We found dishomogenous NG2DsRed perivascular ramifications after SE and compared to control. Concomitantly, PDGFRβ(+) cells re-distributed towards the cerebrovasculature after severe SE. Cerebrovascular NG2DsRed partially colocalized with PDGFRβ(+) while parenchymal PDGFRβ(+) cells did not colocalize with IBA-1(+) microglia. Using in vitro OHC we found decreased NG2 vascular staining and increased PDGFRβ(+) ramifications associated with RECA-1(+) microvessels after seizure-like activity. Cellular PDGFRβ and NG2(+) colocalization was observed in the parenchyma. Finally, analysis of human TLE brains revealed perivascular and parenchymal PDGFRβ(+) cell distributions resembling the murine in vivo and in vitro results. PDGFRβ(+) cells at the cerebrovasculature were more frequent in TLE brain tissues as compared to the autoptic control.
  
  
  CONCLUSIONS
  The rearrangement of PDGFRβ(+) and vascular NG2DsRed cells after SE suggests a possible involvement of pericytes in the cerebrovascular modifications observed in epilepsy. The functional role of vascular-parenchymal PDGFRβ(+) cell redistribution and the relevance of a pericyte response to SE remain to be fully elucidated.
authors.affiliation: Laboratory of Cerebrovascular Mechanisms of Brain Disorders, Department of Neuroscience, Institut de Génomique Fonctionnelle, CNRS UMR5203, INSERM U661, Université Montpellier 1, 2, France.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Milesi
authors.affiliation: Laboratory of Cerebrovascular Mechanisms of Brain Disorders, Department of Neuroscience, Institut de Génomique Fonctionnelle, CNRS UMR5203, INSERM U661, Université Montpellier 1, 2, France.
authors.forename: Badreddine
authors.initials: B
authors.lastname: Boussadia
authors.affiliation: Laboratory of Cerebrovascular Mechanisms of Brain Disorders, Department of Neuroscience, Institut de Génomique Fonctionnelle, CNRS UMR5203, INSERM U661, Université Montpellier 1, 2, France.
authors.forename: Clement
authors.initials: C
authors.lastname: Plaud
authors.affiliation: Laboratory of Cerebrovascular Mechanisms of Brain Disorders, Department of Neuroscience, Institut de Génomique Fonctionnelle, CNRS UMR5203, INSERM U661, Université Montpellier 1, 2, France.
authors.forename: Matthias
authors.initials: M
authors.lastname: Catteau
authors.affiliation: Laboratory of Cerebrovascular Mechanisms of Brain Disorders, Department of Neuroscience, Institut de Génomique Fonctionnelle, CNRS UMR5203, INSERM U661, Université Montpellier 1, 2, France.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Rousset
authors.affiliation: Laboratory of Cerebrovascular Mechanisms of Brain Disorders, Department of Neuroscience, Institut de Génomique Fonctionnelle, CNRS UMR5203, INSERM U661, Université Montpellier 1, 2, France.
authors.forename: Frederic
authors.initials: F
authors.lastname: De Bock
authors.affiliation: Laboratory of Networks and Rhythms in Endocrine Glands, Department of Physiology, Institut de Génomique Fonctionnelle, CNRS UMR5203, INSERM U661, Université Montpellier 1, 2, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Schaeffer
authors.affiliation: Laboratory of Cerebrovascular Mechanisms of Brain Disorders, Department of Neuroscience, Institut de Génomique Fonctionnelle, CNRS UMR5203, INSERM U661, Université Montpellier 1, 2, France.
authors.forename: Mireille
authors.initials: M
authors.lastname: Lerner-Natoli
authors.affiliation: Pathology Department, University Hospital Gui de Chauliac, Montpellier, France.
authors.forename: Valerie
authors.initials: V
authors.lastname: Rigau
authors.affiliation: Laboratory of Cerebrovascular Mechanisms of Brain Disorders, Department of Neuroscience, Institut de Génomique Fonctionnelle, CNRS UMR5203, INSERM U661, Université Montpellier 1, 2, France. Electronic address: nicola.marchi@igf.cnrs.fr.
authors.forename: Nicola
authors.initials: N
authors.lastname: Marchi
mesh_terms: D000328:Adult; D000818:Animals; D000941:Antigens / Q000235:genetics / Q000378:metabolism*; D001808:Blood Vessels / Q000473:pathology; D001812:Blood-Brain Barrier / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D021621:Imaging, Three-Dimensional; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000633:toxicity; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D059906:Neuroimaging; D009474:Neurons / Q000502:physiology; D020286:Pericytes / Q000378:metabolism*; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D013226:Status Epilepticus / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D055815:Young Adult; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D000941:Antigens; D005904:Glial Fibrillary Acidic Protein; D007608:Kainic Acid; D008164:Luminescent Proteins; D011509:Proteoglycans; D020797:Receptor, Platelet-Derived Growth Factor beta; D000099216:Chondroitin Sulfate Proteoglycan 4; C413663:fluorescent protein 583
keywords: Blood–brain barrier; NG2DsRed; PDGFRβ; Pericytes; Status epilepticus
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