PDGFRβ(+) cells in human and experimental neuro-vascular dysplasia and seizures

Abstract

Introduction: 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.

Conclusion: 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.

Keywords: PDGFRβ; neuro-vascular malformations; pericytes; seizures.