Editorial: Glial Dysfunction in Epileptogenesis

Abstract

Editorial on the Research Topic Glial Dysfunction in Epileptogenesis Epilepsy is one of the most common neurological disorders affecting around 1% of the world's population (1). Epilepsy research has so far mainly focused on how to inhibit epileptic discharges resulting in different symptomatic treatment options targeted at neurons. Despite the introduction of more than 20 novel anti-seizure medications since the early 1990s, the proportion of people with drug-refractory epilepsy has remained notably stable at ~30% (2). Given the expanding spectrum of important functions ascribed to the non-neuronal constituents of the brain, we can now observe a paradigm shift where glial cells are included in the equation of epilepsy pathogenesis. With our novel understanding of glial cells as central organizers of homeostatic functions and as major contributors to inflammation and brain excitability, we are approaching novel curative treatment strategies for epilepsy. In the future, targeting dysfunctional and/or reactive glia or glia-mediated inflammatory processes may thus prevent initiation and progression of epilepsy, and yield true anti-epileptogenic medications. In this special issue (SI) of Frontiers in Neurology, we brought together experts in this new area of epilepsy research, and provide a balanced collection of seven original studies and eight review articles. The eBook both starts and ends with reviews of one of the core homeostatic functions of astrocytes, which is glutamate handling in the central nervous system. Glutamate clearance is highly relevant for epilepsy pathogenesis as excess glutamate directly could trigger neuronal discharges and epileptic activity. The first article, presented by Peterson and Binder (USA), provides a systematic overview of the functional components of astrocyte glutamate control. Astrocytes express both glutamate transporters (GLT-1 and GLAST in rodents/EAAT 1 and 2 in humans), as well as metabotropic glutamate receptors (mGluR)3 and mGluR5. Peterson and Binder demonstrate evidence for dysregulation of these channels across patients with epilepsy and preclinical seizure models. After uptake, astrocytes conduct the intracellular metabolization of glutamate and ammonia to glutamine. Sandhu et al. from the group of Tore Eid (USA) highlight the importance of the enzyme glutamine synthetase (GS), and provide evidence for the association of astrocytic GS deficiency or dysfunction in discrete brain regions in several types of epilepsy, including mesial temporal lobe epilepsy, neocortical epilepsies, and glioblastoma-associated epilepsy. These findings are reinforced by several studies using experimental inhibition or deletion of GS in specific brain regions, and by this mimic different human epilepsy forms including their comorbidities. Alcoreza et al. from the group of Harald Sontheimer (USA) provide information on astrocytic glutamate receptor dysregulation in epilepsy, presenting yet another view of the delicate regulatory processes of glutamate homeostasis. They also highlight the importance of extracellular space volume alterations and dysregulation of the water channel aquaporin-4 as integral parts of epilepsy pathophysiology and discuss evidence for upregulation of system x–c, a cystine/glutamate antiporter expressed by astrocytes in epileptic tissue. Kinboshi et al. (Japan) focuses on another important homeostatic function of astrocytes, which is K⁺ spatial buffering. This process mainly depends on inwardly rectifying potassium (Kir) 4.1 channels and gap junction coupling. Astrocytes rapidly transport K⁺ from areas of high neuronal activity, where [K⁺]_EC increases, to regions with lower K⁺ levels via the astrocyte network through gap junctions. This K⁺ clearance mechanism is not only critical for maintaining K⁺ homeostasis and preventing neural hyperexcitability but is also linked to glutamate uptake during normal brain function. There is ample evidence for Kir4.1 dysfunction in epilepsy and recent studies indicate that inhibition of Kir4.1 channels facilitates the expression of brain-derived neurotrophic factor (BDNF), an important modulator of epileptogenesis in astrocytes. Verhoog et al. from the group of Erwin van Vliet (The Netherlands) enriches this eBook with a substantial review of state-of-the-art literature on dysfunctional astrocytes in epilepsy, also including the role astrocyte Ca²⁺ signaling, altered blood brain barrier (BBB) function and blood flow regulation. The series of contributions to this eBook on glia-derived inflammation in epilepsy could not have a better opening than with an original study on febrile seizures, provided by Brennan et al. from the group of Tallie Baram (USA). The potential role of aberrant microglia and astrocyte function during epileptogenesis is important because the involved mediators provide targets for intervention and prevention of epilepsy. By performing experimental febrile status epilepticus in rat pups, the authors elicited a strong inflammatory response leading to a rapid and sustained upregulation of pro-inflammatory cytokines. In the attempt to curb epileptogenesis, several pathways involving cytokines, microRNAs, high mobility group B-1 (HMGB1) and prostaglandin E2 signaling were targeted by using network-specific interventions as well as global anti-inflammatory approaches. The failure of selectively decreasing the expression of downstream inflammatory cascades, and the emergence of intolerable side effects, illustrates that the intricate, cell-specific and homeostatic interplays among these networks constitute a serious challenge to tailored interventions that aim to prevent epileptogenesis. Another approach to curb epileptogenesis is presented in the study of Wyatt-Johnson et al. (USA). Microglial survival and proliferation are regulated by the colony-stimulating...