Glutamate and tumor-associated epilepsy: glial cell dysfunction in the peritumoral environment

Abstract

Seizures are a serious and debilitating co-morbidity of primary brain tumors that affect most patients, yet their etiology is poorly understood. In many CNS pathologies, including epilepsy and brain injury, high levels of extracellular glutamate have been implicated in seizure generation. It has been shown that gliomas release neurotoxic levels of glutamate through their high expression of system xc-. More recently it was shown that the surrounding peritumoral cortex is spontaneously hyperexcitable. In this review, we discuss how gliomas induce changes in the surrounding environment that may further contribute to elevated extracellular glutamate and tumor-associated seizures. Peritumoral astrocytes become reactive and lose their ability to remove glutamate, while microglia, in response to signals from glioma cells, may release glutamate. In addition, gliomas increase blood brain barrier permeability, allowing seizure-inducing serum components, including glutamate, into the peritumoral region. These factors, working together or alone, may influence the frequency and severity of tumor-associated epilepsy.

Keywords: Astrocytes; Glioma; Gliosis; Glutamate; Hyperexcitability; Seizures.

Fig 1. Animals implanted with human glioma cells show spontaneous epileptic activity

A) EEG recording of a seizure from a mouse intracranially-implanted with GBM22 human glioma cells, 15 d after implantation, and B) EEG recording showing typical spontaneous spiking in a mouse intracranially-implanted with the human glioma cell line U251

Fig 2. Peritumoral astrocytes and microglia are activated

A, A′ and A″) Microglia of tumor-implanted animals are positive for Iba1 and Cd11b. They are enriched at the tumor border and enter the GFP-positive tumor mass. B and B′) Gray matter astrocytes surrounding a glioma 3 wk after D54 tumor cell implantation become hypertroph and upregulate the intermediate filament GFAP. C) Unaffected astrocytes of the contralateral hemisphere are negative for GFAP.