PDGFRβ(+) cells in human and experimental neuro-vascular dysplasia and seizures.
BACKGROUND
Neuro-vascular rearrangement occurs in brain disorders, including epilepsy. Platelet-derived growth factor receptor beta (PDGFRβ) is used as a marker of perivascular pericytes. Whether PDGFRβ(+) cell reorganization occurs in regions of neuro-vascular dysplasia associated with seizures is unknown.


METHODS
We used brain specimens derived from epileptic subjects affected by intractable seizures associated with focal cortical dysplasia (FCD) or temporal lobe epilepsy with hippocampal sclerosis (TLE-HS). Tissues from cryptogenic epilepsy, non-sclerotic hippocampi or peritumoral were used for comparison. An in vivo rat model of neuro-vascular dysplasia was obtained by pre-natal exposure to methyl-axozy methanoic acid (MAM). Status epilepticus (SE) was induced in adult MAM rats by intraperitoneal pilocarpine. MAM tissues were also used to establish organotypic hippocampal cultures (OHC) to further assess pericytes positioning at the dysplastic microvasculature. PDGFRβ and its colocalization with RECA-1 or CD34 were used to segregate perivascular pericytes. PDGFRβ and NG2 or IBA1 colocalization were performed. Rat cortices and hippocampi were used for PDGFRβ western blot analysis.


RESULTS
Human FCD displayed the highest perivascular PDGFRβ immunoreactivity, indicating pericytes, and presence of ramified PDGFRβ(+) cells in the parenchyma and proximal to microvessels. Tissues deriving from human cryptogenic epilepsy displayed a similar pattern of immunoreactivity, although to a lesser extent compared to FCD. In TLE-HS, CD34 vascular proliferation was paralleled by increased perivascular PDGFRβ(+) pericytes, as compared to non-HS. Parenchymal PDGFRβ immunoreactivity co-localized with NG2 but was distinct from IBA1(+) microglia. In MAM rats, we found pericyte-vascular changes in regions characterized by neuronal heterotopias. PDGFRβ immunoreactivity was differentially distributed in the heterotopic and adjacent normal CA1 region. The use of MAM OHC revealed microvascular-pericyte dysplasia at the capillary tree lining the dentate gyrus (DG) molecular layer as compared to control OHC. Severe SE induced PDGFRβ(+) immunoreactivity mostly in the CA1 region of MAM rats.


CONCLUSIONS
Our descriptive study points to microvascular-pericyte changes in the epileptic pathology. The possible link between PDGFRβ(+) cells, neuro-vascular dysplasia and remodeling during seizures is discussed.
Clinical Epileptology and Experimental Neurophysiology, Department of Neurosurgery, Istituto Neurologico Besta, Milan, Italy.
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Garbelli
Laboratory of Cerebrovascular Mechanisms of Brain Disorders, Department of Neuroscience, Institute of Functional Genomics, Montpellier (CNRS-INSERM), France.
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F
de Bock
Clinical Epileptology and Experimental Neurophysiology, Department of Neurosurgery, Istituto Neurologico Besta, Milan, Italy.
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Medici
Laboratory of Cerebrovascular Mechanisms of Brain Disorders, Department of Neuroscience, Institute of Functional Genomics, Montpellier (CNRS-INSERM), France.
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Rousset
Clinical Epileptology and Experimental Neurophysiology, Department of Neurosurgery, Istituto Neurologico Besta, Milan, Italy.
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Villani
Laboratory of Cerebrovascular Mechanisms of Brain Disorders, Department of Neuroscience, Institute of Functional Genomics, Montpellier (CNRS-INSERM), France.
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Boussadia
Laboratory of Stress, Hormones and Plasticity, Department of Physiology, Institute of Functional Genomics, Montpellier, France.
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Arango-Lievano
Laboratory of Stress, Hormones and Plasticity, Department of Physiology, Institute of Functional Genomics, Montpellier, France.
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Jeanneteau
Departments of Neurosciences and Pharmacology, University of California, UCSD, USA.
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Daneman
Clinical Neurophysiology, Hospital La Timone, Marseille, France.
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Bartolomei
Laboratory of Cerebrovascular Mechanisms of Brain Disorders, Department of Neuroscience, Institute of Functional Genomics, Montpellier (CNRS-INSERM), France. Electronic address: nicola.marchi@igf.cnrs.fr.
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Marchi
D000293:Adolescent; D000328:Adult; D000818:Animals; D002135:Calcium-Binding Proteins; D002540:Cerebral Cortex / Q000002:abnormalities / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000150:complications / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D006624:Hippocampus / Q000098:blood supply / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007223:Infant; D054220:Malformations of Cortical Development / Q000150:complications / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008840:Microfilament Proteins; D020286:Pericytes / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D012640:Seizures / Q000150:complications; D055815:Young Adult
C112986:AIF1 protein, human; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D008840:Microfilament Proteins; C000605860:PDGFRB protein, human; D020797:Receptor, Platelet-Derived Growth Factor beta
PDGFRβ; neuro-vascular malformations; pericytes; seizures