Altered Spontaneous Glutamatergic and GABAergic Activity in the Peritumoral Cortex of Low-Grade Gliomas Presenting With History of Seizures.

Soumil Dey,Meher Chand Sharma,Manjari Tripathi,Aparna Banerjee Dixit,Ramesh Sharanappa Doddamani,P Sarat Chandra,Jyotirmoy Banerjee

doi:10.3389/fnins.2021.689769

Soumil Dey, Meher Chand Sharma + Show 5 more

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https://doi.org/10.3389/fnins.2021.689769

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Abstract

The peritumoral regions of WHO grade II gliomas, like astrocytoma and oligodendroglioma, have been reported to show epileptiform activities. An imbalance of glutamatergic and GABAergic mechanisms is primarily responsible for the generation of epileptiform activities. Here we have compared the electrophysiological properties of pyramidal neurons in intraoperative peritumoral specimens obtained from glioma patients with (GS) and without (GN) a history of seizures at presentation. Histology and immunohistochemistry were performed to assess the infiltration of proliferating cells at the peritumoral tissues. Whole-cell patch clamp technique was performed to measure the spontaneous glutamatergic and GABAergic activity onto pyramidal neurons in the peritumoral samples of GS (n = 11) and GN (n = 15) patients. The cytoarchitecture of the peritumoral tissues was devoid of Ki67 immuno-positive cells. We observed a higher frequency of spontaneous glutamatergic and GABAergic activities onto pyramidal neurons of the peritumoral samples of GS patients. Our findings suggest that, in spite of similar histopathological features, the pyramidal neurons in the peritumoral samples of GS and GN patients showed differences in spontaneous excitatory and inhibitory synaptic neurotransmission. An alteration in postsynaptic currents may contribute to the spontaneous epileptiform activity in GS patients.

Highlights

Low-grade gliomas (LGG), like oligodendrogliomas (ODG) and astrocytomas, usually present with a history of multiple seizures apart from other neurological symptoms (van Breemen et al, 2007)
It might be possible that the higher level of the extracellular glutamate stimulates the postsynaptic glutamate receptors, which was reflected in the higher amplitude of sEPSCs in the peritumoral samples obtained from glioma patients with (GS) patients
Extracellular GABA levels are reported to be higher in the peritumoral tissues than in the tumor core (Bianchi et al, 2004), possibly due to the increased action potential-dependent GABA release as indicated by the higher frequency of sIPSCs in the peritumoral samples obtained from GS patients as compared to that in GN (Figures 2B,E)

Summary

Introduction

Low-grade gliomas (LGG), like oligodendrogliomas (ODG) and astrocytomas, usually present with a history of multiple seizures apart from other neurological symptoms (van Breemen et al, 2007). The mutation of isocitrate dehydrogenase 1 (IDH-1) gene leads to the accumulation of D-2-hydroxyglutarate in glioma cells, which acts as agonist of glutamate receptors when the extracellular concentration of glutamate is not increased (Dang et al, 2009; Chen et al, 2017), contributing to hyperexcitability and seizure generation (Huberfeld and Vecht, 2016). Dysregulated chloride homeostasis contributes to abnormal GABAergic signaling and depolarizes pyramidal neurons in peritumoral tissues, thereby contributing to seizure generation (Huberfeld and Vecht, 2016). We have previously shown that the spontaneous glutamatergic activity in cortical tissue samples obtained from mesial temporal lobe epilepsy patients was higher compared to that in the case of peritumoral tissue samples obtained from glioma patients without a history of seizures (Banerjee et al, 2015, 2017, 2020). Despite similar histopathological features, there would be differences in spontaneous glutamatergic and GABAergic neurotransmission when comparing pyramidal neurons from the peritumoral samples of GS patients with that in the case of GN patients

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