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Given the important functions that glutamate serves in excitatory neurotransmission, understanding the regulation of glutamate in physiological and pathological states is critical to devising novel therapies to treat epilepsy. Exclusive expression of pyruvate carboxylase and glutamine synthetase in astrocytes positions astrocytes as essential regulators of glutamate in the central nervous system (CNS). Additionally, astrocytes can significantly alter the volume of the extracellular space (ECS) in the CNS due to their expression of the bi-directional water channel, aquaporin-4, which are enriched at perivascular endfeet. Rapid ECS shrinkage has been observed following epileptiform activity and can inherently concentrate ions and neurotransmitters including glutamate. This review highlights our emerging knowledge on the various potential contributions of astrocytes to epilepsy, particularly supporting the notion that astrocytes may be involved in seizure initiation via failure of homeostatic responses that lead to increased ambient glutamate. We also review the mechanisms whereby ambient glutamate can influence neuronal excitability, including via generation of the glutamate receptor subunit GluN2B-mediated slow inward currents, as well as indirectly affect neuronal excitability via actions on metabotropic glutamate receptors that can potentiate GluN2B currents and influence neuronal glutamate release probabilities. Additionally, we discuss evidence for upregulation of System xc-, a cystine/glutamate antiporter expressed on astrocytes, in epileptic tissue and changes in expression patterns of glutamate receptors. NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [1R01CA227149-01A1, 1R01NS036692-01A1]; DODUnited States Department of Defense [W81XWH-18-1-0521] This work was supported by NIH grants 1R01CA227149-01A1 and 1R01NS036692-01A1, and DOD grant W81XWH-18-1-0521.

Epileptic seizures are among the most common presenting symptom in patients with glioma. The etiology of glioma‐related seizures is complex and not completely understood. Studies using adult glioma patient tissue and adult glioma mouse models, show that neurons adjacent to the tumor mass, peritumoral neurons, are hyperexcitable and contribute to seizures. Although it is established that there are phenotypic and genotypic distinctions in gliomas from adult and pediatric patients, it is unknown whether these established differences in pediatric glioma biology and the microenvironment in which these glioma cells harbor, the developing brain, differentially impacts surrounding neurons. In the present study, we examine the effect of patient‐derived pediatric glioma cells on the function of peritumoral neurons using two pediatric glioma models. Pediatric glioma cells were intracranially injected into the cerebrum of postnatal days 2 and 3 (p2/3) mouse pups for 7 days. Electrophysiological recordings showed that cortical layer 2/3 peritumoral neurons exhibited significant differences in their intrinsic properties compared to those of sham control neurons. Peritumoral neurons fired significantly more action potentials in response to smaller current injection and exhibited a depolarization block in response to higher current injection. The threshold for eliciting an action potential and pharmacologically induced epileptiform activity was lower in peritumoral neurons compared to sham. Our findings suggest that pediatric glioma cells increase excitability in the developing peritumoral neurons by exhibiting early onset of depolarization block, which was not previously observed in adult glioma peritumoral neurons., The effect of pediatric glioma cells on the function of surrounding neurons during early development is unknown. We intrancranially injected patient‐derived pediatric glioma cells in young pups and examined on the function of peritumoral neurons. Pediatric glioma cells induced changes in the intrinsic properties of periturmoral neurons, lowered the threshold of hyperexcitability and exhibited an early onset of depolarization block.

Objective: Currently prescribed antiepileptic drugs (AEDs) are ineffective in treating approximately 30% of epilepsy patients. Sulfasalazine (SAS) is an US Food and Drug Administration (FDA)–approved drug for the treatment of Crohn disease that has been shown to inhibit the cystine/glutamate antiporter system xc‐ (SXC) and decrease tumor‐associated seizures. This study evaluates the effect of SAS on distinct pharmacologically induced network excitability and determines whether it can further decrease hyperexcitability when administered with currently prescribed AEDs. Methods: Using in vitro cortical mouse brain slices, whole‐cell patch‐clamp recordings were made from layer 2/3 pyramidal neurons. Epileptiform activity was induced with bicuculline (bic), 4‐aminopyridine (4‐AP) and magnesium‐free (Mg2+‐free) solution to determine the effect of SAS on epileptiform events. In addition, voltagesensitive dye (VSD) recordings were performed to characterize the effect of SAS on the spatiotemporal spread of hyperexcitable network activity and compared to currently prescribed AEDs. Results: SAS decreased evoked excitatory postsynaptic currents (eEPSCs) and increased the decay kinetics of evoked inhibitory postsynaptic currents (eIPSCs) in layer 2/3 pyramidal neurons. Although application of SAS to bic and Mg2+‐free–induced epileptiform activity caused a decrease in the duration of epileptiform events, SAS completely blocked 4‐AP–induced epileptiform events. In VSD recordings, SAS decreased VSD optical signals induced by 4‐AP. Co‐application of SAS with the AED topiramate (TPM) caused a significantly further decrease in the spatiotemporal spread of VSD optical signals. Significance: Taken together this study provides evidence that inhibition of SXC by SAS can decrease network hyperexcitability induced by three distinct pharmacologic agents in the superficial layers of the cortex. Furthermore, SAS provided additional suppression of 4‐AP–induced network activity when administered with the currently prescribed AED TPM. These findings may serve as a foundation to assess the potential for SAS or other compounds that selectively target SXC as an adjuvant treatment for epilepsy. Foundation for the National Institutes of Health, Grant/Award Number: 5R01‐NS036692, R01‐NS052634 and R01CA227149

Epilepsy is a neurological disorder afflicting ~65 million people worldwide. It is caused by aberrant synchronized firing of populations of neurons primarily due to imbalance between excitatory and inhibitory neurotransmission. Hence, the historical focus of epilepsy research has been neurocentric. However, the past two decades have enjoyed an explosion of research into the role of glia in supporting and modulating neuronal activity, providing compelling evidence of glial involvement in the pathophysiology of epilepsy. The mechanisms by which glia, particularly astrocytes and microglia, may contribute to epilepsy and consequently could be harnessed therapeutically are discussed in this Review.

Brain tumor patients commonly present with epileptic seizures. We show that tumor-associated seizures are the consequence of impaired GABAergic inhibition due to an overall loss of peritumoral fast spiking interneurons (FSNs) concomitant with a significantly reduced firing rate of those that remain. The reduced firing is due to the degradation of perineuronal nets (PNNs) that surround FSNs. We show that PNNs decrease specific membrane capacitance of FSNs permitting them to fire action potentials at supra-physiological frequencies. Tumor-released proteolytic enzymes degrade PNNs, resulting in increased membrane capacitance, reduced firing, and hence decreased GABA release. These studies uncovered a hitherto unknown role of PNNs as an electrostatic insulator that reduces specific membrane capacitance, functionally akin to myelin sheaths around axons, thereby permitting FSNs to exceed physiological firing rates. Disruption of PNNs may similarly account for excitation-inhibition imbalances in other forms of epilepsy and PNN protection through proteolytic inhibition may provide therapeutic benefits., Brain tumours are associated with epilepsy. Here the authors show, using a mouse model, that the degradation of perineuronal nets around fast spiking interneurons near the tumour contribute to seizures by increasing their membrane capacitance and firing.