Aberrant neuronal differentiation is common in glioma but is associated neither with epileptic seizures nor with better survival

Christoph Patrick Beier,Rikke Hedegaard Dahlrot,Per Svenningsen,Sólborg Berglind Heimisdóttir,Mai Froberg Sørensen,Markus J Riemenschneider,Tine Rasmussen,Bjarne Winther Kristensen,Julie Slinning Aarø,Mia Dahl Sørensen,Helene Broch Tenstad,Dagmar Beier

doi:10.1038/s41598-018-33282-5

Christoph Patrick Beier, Rikke Hedegaard Dahlrot + Show 10 more

Open Access

https://doi.org/10.1038/s41598-018-33282-5

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Abstract

The mechanisms of glioma-associated seizures (GAS) have yet to be fully elucidated. Proneural subtype, isocitrate dehydrogenase 1 (IDH1) mutations, and epileptic seizures are closely associated suggesting that aberrant neuronal differentiation contributes to glioma-associated seizures. In a population-based cohort (n = 236), lack of stem cell marker expression (nestin, musashi) was significantly associated with IDH1 mutations and GAS at diagnosis. In vitro data suggested an association of IDH1 mutations and a more differentiated phenotype. Out of eight glioma stem cell (GSC) lines, seven revealed positivity for the synaptic marker protein synaptophysin. Three had synapse-like structures identified by electron microscopy and were either vGlut1 (glutamatergic) or GAD67 (GABAergic) positive. In vivo, >10% synaptophysin-positive tumour cells were present in >90% of all gliomas. Synaptophysin expression was associated with proneural subtype and vGlut1 expression, suggesting that most synapse-like structures in glioma are glutamatergic. However, we found null associations between vGlut1 protein/mRNA expression and survival, GAS at onset, development of GAS after resection, and refractory GAS. Synapse-like structures were neither functional nor activated by spontaneous action potentials or cellular networks. Thus, aberrant neuronal differentiation including glutamatergic synapse-like structures is detectable in glioma but is associated neither with epileptic seizures nor with better survival.

Highlights

The mechanisms of glioma-associated seizures (GAS) have yet to be fully elucidated
This provides an elegant explanation for the increased epileptogenicity of isocitrate dehydrogenase 1 (IDH1) mutant glioma, the D2HG concentrations needed for activation of NMDA receptors in vitro (10 mM) have been higher than the actual D2HG concentrations measured in the CNS of patients (1–6 mM)[16,18]
We studied the association of the stem cell markers nestin and musashi-1 with epileptic seizures at diagnosis in a cohort comprising 239 patients with gliomas (WHO II-IV, overview over patients: Supplementary Table 1, previously reported in26)

Summary

Introduction

The mechanisms of glioma-associated seizures (GAS) have yet to be fully elucidated. Proneural subtype, isocitrate dehydrogenase 1 (IDH1) mutations, and epileptic seizures are closely associated suggesting that aberrant neuronal differentiation contributes to glioma-associated seizures. Synaptophysin expression was associated with proneural subtype and vGlut[1] expression, suggesting that most synapse-like structures in glioma are glutamatergic. Aberrant neuronal differentiation including glutamatergic synapse-like structures is detectable in glioma but is associated neither with epileptic seizures nor with better survival. XCT expression is only associated with GAS at diagnosis but neither with refractory seizures nor with the development of seizures after resection[12] This stresses the need for identification of contributing factors causing GAS. Chen et al could recently show that D-2-hydroxyglutarate (D2HG), the product of mutant IDH1, is able to directly activate N-methyl-D-aspartate (NMDA) receptors This provides an elegant explanation for the increased epileptogenicity of IDH1 mutant glioma, the D2HG concentrations needed for activation of NMDA receptors in vitro (10 mM) have been higher than the actual D2HG concentrations measured in the CNS of patients (1–6 mM)[16,18]

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