Glial regenerative cell types in the superficial cortex in cortical dysplasia subtypes

Joan Y.W Liu,Cheryl Reeves,Rianne Van Der Pijl,Maria Thom

doi:10.1016/j.eplepsyres.2020.106529

Joan Y.W Liu, Cheryl Reeves + Show 2 more

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https://doi.org/10.1016/j.eplepsyres.2020.106529

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Abstract

PurposeFocal Cortical Dysplasias (FCD) are localized malformative brain lesions in epilepsy. FCD3a associated with hippocampal sclerosis, affects the superficial cortex and is presumed to have an ‘acquired’ rather than developmental origin. Precursor cells may arise outside neurogenic zones including cortical layer I. Our aim was to characterise subsets of glial progenitor cells in the superficial cortical layers, known to be involved in gliosis and gliogenesis and that could distinguish FCD3a from other subtypes. MethodsUsing immunohistochemistry we quantified the density of glial progenitor subsets in superficial cortex layers using markers against PAX6, GFAP, Olig2 and PDGFRβ and proliferation marker MCM2 in ten FCD3a cases compared to 18 other FCD types and 11 non-FCD controls. Key findingsGlial progenitor cells types were present in the cortical layer I and II in all FCD groups. GFAP cells frequently expressed PAX6 and significantly higher GFAP/PAX6 than GFAP/MCM2 cell densities were identified in the FCD3a group (p < 0.05). Olig2 cell densities were significantly higher in FCD3b than FCD3a (p = 0.002) and significantly higher GFAP/MCM2 compared to PDGFRβ/MCM2 cell densities were identified in both FCD3b and FCD2 groups. There was no correlation between cell densities and the age of patients at surgery and between cortical regions. SignificanceImmature and proliferative glial populations across FCD variants reflect reactive cell types and differences may provide insight into underlying pathomechanisms. Higher PAX6 expression in astroglial cells in FCD3a may indicate a switch to astrocytic maturation and enhanced superficial gliosis. Higher Olig2 and GFAP/MCM2 densities in FCD3b may reflect margins of the tumour infiltration zone rather than true cortical dysplasia.

Highlights

Focal cortical dysplasia (FCD) type 3a is a cytoarchitectural change encountered in approximately 10 % of patients with Temporal Lobe Epilepsy and Hippocampal Sclerosis (TLE/hippocampal sclerosis (HS))
The superficial cortical layers are highly relevant to seizure propagation through extensive cortical-cortical networks and generation of slow rhythms (Halgren et al, 2018) ; discharges from the superficial cortex spread over a larger area than deeper cortex (Serafini et al, 2015), recruitment of layer II/III neurones plays a critical role in seizure spread (Brodovskaya and Kapur, 2019) and activation of cAMP-response element binding protein, a neuronal activity biomarker, was recently shown only in layer II neurones of epilepsy surgical resections (De Santis et al, 2020)
paired-box transcription factor 6 (PAX6), MCM2, GFAP, Olig2 and PDGFRβlabelled cells were observed in the superficial cortex in FCD3a (Fig. 1) and other FCD types

Summary

Introduction

Focal cortical dysplasia (FCD) type 3a is a cytoarchitectural change encountered in approximately 10 % of patients with Temporal Lobe Epilepsy and Hippocampal Sclerosis (TLE/HS). FCD3a principally in volves the superficial cortical layers with abnormal clustering of neu rones in layer II, reduction of neurones in the lower part of layer II/III and accompanying laminar gliosis (Blumcke et al, 2011). This FCD pattern has been argued to represent an acquired post-natal reorgan izational dysplasia, impairing normal maturation, likely to be both aetiologically and temporally linked with the development of HS, its functional significance remains unclear (Thom et al, 2009).

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