Christoph Patrick Beier, Tine Rasmussen, Rikke Hedegaard Dahlrot, Helene Broch Tenstad, Julie Slinning Aarø, Mai Froberg Sørensen, Sólborg Berglind Heimisdóttir, Mia Dahl Sørensen, Per Svenningsen, Markus J. Riemenschneider, Dagmar Beier, Bjarne Winther Kristensen
NeurologyDepartment of Clinical ResearchPathologyOncologyKardiovaskulær og Renal ForskningDepartment of Molecular Medicine
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.
https://www.nature.com/articles/s41598-018-33282-5