Early glial dysfunction in epilepsy

Abstract

Since its inception in the 19th century, modern epilepsy research has been decidedly neurocentric. Almost without exception and to this day, efforts to understand the development and manifestations of seizure activity have focused exclusively on the dysfunction, structural damage, and, ultimately, death of nerve cells. This sentiment is entirely sensible since it is difficult to argue against the central role of abnormal electrical discharges in the many expressions and symptoms of clinical epilepsy. And since neurons, and only neurons, are capable of conducting electrical activity in the brain, there appears to be no need to look elsewhere for the key to pathophysiology. This exclusive concentration on neurons must now be reevaluated in light of recent discoveries in the basic neurosciences. It has become clear that neuronal function—and by extension neuronal dysfunction—is tightly modulated, in fact controlled, by a number of nonneuronal cells. Many of these are glial cells, which in the human brain outnumber neurons by a ratio of approximately 10:1. Contrary to conventional thought, which had considered glia mainly as structural scaffolds, potassium sinks and nutritional resources for neurons, these cells participate actively in synapse development, regulate blood–brain barrier function, and play prominent roles in neurodegenerative processes. Consequently, the study of astrocytes, microglial cells, and oligodendrocytes, the three major glial cell types, has become a major focus of contemporary neuroscience research (Kettenmann & Ransom, 2005). The epileptic brain has long been known to present with gliosis, i.e., scar tissue composed of nonneuronal, presumably glial, cells. However, gliosis was traditionally viewed as an inconsequential reaction to seizure-related neuronal injury or degeneration and was considered irrelevant to the etiology of the disease. It was not until the late 1970s that glial cells were first regarded as active participants in the pathogenic process (Brotchi, 1979), and the stream of new information on glial biology has increasingly influenced the thinking of leading epilepsy researchers. Collectively, noninvasive imaging technology, the use of modern electrophysiological methodologies in animals and humans, and the revolution in molecular biology and genetics, have provided significant and complementary information suggesting a pathophysiologically significant role of glia in the development and maintenance of the epileptic condition. Several lines of evidence suggest that astrocytes, which normally play a critical role in neurotransmission as integral components of the so-called “tripartite synapse,” participate actively in seizure progression. This concept evolved from a large number of observations demonstrating that acute seizures trigger astrocytic changes, which in turn cause either seizure reduction or further aggravation. These changes, which range from subtle structural abnormalities and chemical malfunctions to cellular hypertrophy and proliferation, are often rapid in onset and occasionally transient, but frequently persist until and beyond the occurrence of spontaneous, repetitive seizure activity. Interestingly, these astrocytic transformations are not always restricted to areas of the limbic seizure circuit, such as the hippocampus and the parahippocampal region, and are not necessarily associated with overt neuronal loss or injury. The challenges to generate a comprehensive hypothesis of the complex role of astrocytes in the development of the epileptic condition are therefore formidable. While only very few studies indicate an important role of oligodendrocytes, it appears that microglial cells, the resident immune cells of the brain, too, are critical players in epilepsy. As a major source of paracrine signals releasing pro- and anticonvulsive cytokines, growth factors, and other neuroactive peptides and proteins, these agile cells are thought not only to influence neuronal communication in the normal brain, but also to facilitate the excessive electrical discharges characteristic of epileptic phenomena. Like in the case of astrocytes, the experimental evidence so far mainly speaks to the participation of reactive microglial cells in the development of epilepsy. In other words, most studies were designed to document and understand the cells' ability to accelerate or reduce the development of prolonged seizure activity following a primary trigger, convulsive or otherwise. Influenced by experimental studies in models of neurodegenerative diseases (see review by Lobsiger & Cleveland, 2007), several epilepsy researchers recently began to ask the question if glial cells—again primarily astrocytes and microglia—might also play a part in seizure initiation. Bordering on blasphemy in light of century-old assumptions, this question implies that selective glial impairment(s) in the seizure-naive brain may elicit secondary epileptic discharges in neurons and neuronal networks. If verified, this provocative concept would clearly have important ramifications for the preclinical study of epileptogenic mechanisms. Furthermore, demonstration of a causative role of glial cells in epileptogenesis would immediately suggest interventional strategies targeting glia-specific processes in high-risk populations. The present supplement of Epilepsia summarizes some of the latest developments in this exciting area of epileptogenesis research. Based on an Investigators' Workshop at the 2006 meeting of the American Epilepsy Society and authored by major basic and clinical researchers in the field, the papers provide state-of-the-art vignettes of the “early glial dysfunction” hypothesis. Using distinct experimental approaches, the authors have identified and described glial proteins and messenger molecules, which may play singular or joint roles in epileptogenesis. Collectively, these studies provide converging evidence in support of a very early, and in some cases primary, involvement of glial dysfunction in seizure initiation. These chapters will also alert the reader to the experimental difficulties, which are inherent to the exploration of recurrent, mutual interactions between glial cells and abnormally discharging neurons. It is the goal of the following articles to raise awareness of these exciting new developments and challenges in the epilepsy research community, and to entice both seasoned and new investigators to incorporate glia-related concepts in their experimental strategies. Conflict of interest: The author declares no conflicts of interest.