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Astrocytes and Epilepsy

By: , Posted on: August 16, 2016

Epilepsy

For a long time, neurons were considered the principal cell type in the brain and glial cells were simply the “glue” that held them together.  Now, however, glial cells are recognized as participating in a myriad of functions, including shaping the strength of synaptic transmission.  In fact, insofar as they contact many synapses simultaneously, astrocytes may be the “conductors” of the neuronal symphony.  Similarly, in ancient times, a patient with seizures was considered insane or demonically possessed.  This has of course changed and now epilepsy is considered a group of disorders characterized by abnormally synchronized neuronal activity that presents as seizures.  New insights into brain function and our current understanding of epilepsy is in large part to a number of brilliant scientists.  In our new book Astrocytes and Epilepsy, we bring together historical and modern developments in astrocyte biology and marry these with recent groundbreaking development in the “glioscience” of epilepsy.

The first chapter of the book, entitled History of Astrocytes, details the history and evolution of concepts of neuroglia in the context of the “neuron doctrine”.  The contributions of many notable scientists, including Rudolf Virchow, Santiago Ramón y Cajal, and Pío del Río-Hortega are described.  Thanks to these great minds, we have a better understanding of the cellular composition of the brain and the roles of both glia and neurons.

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Glial cells are now known to be a diverse group of non-neuronal cells with each subtype exhibiting varying degrees of structural and functional heterogeneity.  In particular, astrocytes, or star-shaped cells, encompass multiple types of structurally and functionally distinct cells.  The diversity of astrocytes is detailed in Chapter 2:  Astrocytes in the mammalian brain.

Neurons are the only electrically excitable cell type in the brain, producing “all-or-none” action potentials in response to drastic changes in the membrane potential.   Glia cannot produce action potentials, but research conducted over the last few decades have demonstrated that astrocytes are not entirely passive.  Instead, these cells can also release neurotransmitters in a process called gliotransmission.  This discovery greatly changed the way scientists viewed astrocytes.  Evidence supporting the concept of gliotransmission is chronicled in Chapter 3:  Gliotransmitters.  A key discovery in 1990 by Ann Cornell-Bell and her colleagues led to our current understanding of long-range glial signaling in the brain.  After that, several other researchers contributed evidence to support gliotransmission and detailed a variety of mechanisms by which gliotransmitters are released.  In addition to these key discoveries, the controversy over gliotransmission is also discussed in this chapter.

Epilepsy is not just a single disease, but instead is a group of disorders, all of which are characterized by the unpredictable occurrence of seizures.  Types of epilepsies and methods of classification are detailed in Chapter 4:  Types of epilepsy and Chapter 5:  Neuropathology of human epilepsy.  Affecting about 2% of the world’s population, epilepsy impacts more people than multiple sclerosis, cerebral palsy, muscular dystrophy, and Parkinson’s disease combined.  Despite the high prevalence, epilepsy is still widely misunderstood.  Fortunately, this is changing.  Due to the excitable nature of neurons, epilepsy was always considered a neuronal disease.  Now, however, the role of glial cells is appreciated.  For example, calcium signaling and gliotransmission from astrocytes become perturbed in the epileptic brain.  The roles of metabotropic glutamate receptors, propagating calcium waves, and the release of gliotransmitters from astrocytes in maintaining neuronal excitability are discussed in Chapter 6:  Astrocyte calcium signaling.

Astrocytes are now known to express a variety of ion channels, including K+, Na+, Ca2+, and Cl channels.  These primarily serve to maintain ion homeostasis in the brain.  Alterations in the extracellular levels of ions, however, can lead to changes in the membrane potentials and neuronal hyperexcitability.  Types of K+ channels, their role in K+ homeostasis, and how they become altered in epileptic tissue are detailed in Chapter 7:  Potassium channels.  Not surprisingly, ion homeostasis is linked to osmotic regulation and water balance.  Aquaporins are water channels that aid in fluid transport in response to changes in the osmotic gradient.  The main water channel in the central nervous system is aquaporin-4 (AQP4) and it is highly expressed at specialized domains that contact blood vessels, ventricles, and other areas of the brain where fluid transport is crucial.  Largely through study of mice deficient in AQP4 (AQP4-/- mice), several different functions of AQP4 in the brain have been elucidated.  AQP4-/- mice exhibited reduced osmotic water permeability, impaired water clearance, altered extracellular space properties, and a worsened seizure phenotype.  The crucial experiments that led to our understanding of the role of AQP4 in the healthy and epileptic brain are detailed in Chapter 8:  Water channels.

In addition to clearing ions from the extracellular space, astrocytes are primarily responsible for the uptake of neurotransmitters.  Glutamate is considered the main excitatory neurotransmitter in the brain.  After neuronal activity, glutamate is taken up by astrocytes by key glutamate transporters and it is further metabolized.  The role of metabolic communication between neurons and astrocytes, the fate of glutamate in the brain, and altered glutamate homeostasis in epilepsy are described in Chapter 9:  Glutamate metabolism. 

Adenosine is a key neuromodulator involved in energy metabolism in the brain.  It is considered a natural anticonvulsant because it suppresses neuronal excitability.  An orchestra of enzymes, including adenosine kinase and 5’-nucleotidase, work together harmoniously to regulate extracellular adenosine levels.  When this orchestra is disrupted, adenosine levels fall and the brain experiences neuronal hyperexcitability.  Focal manipulation of adenosine metabolism has recently been considered a promising new treatment option for epilepsy.  Adenosine augmentation therapies may offer the epileptic brain both neuroprotection and seizure reduction, potentially preventing their occurrence altogether.  In Chapter 10:  Adenosine metabolism, the role of adenosine receptors and enzymes and their dysregulation in the epileptic brain are considered.  This chapter also offers insight into many different therapeutic strategies that we hope to soon see as common antiepileptic treatment options for patients.

Epilepsy

The healthy brain has several ways to communicate, but the main forms of cell-to-cell coupling is through gap junctions.  These junctions may form between two cells that are the same (such as neuron-neuron) or different (such as astrocyte-oligodendrocyte) cell type.  The primary astrocyte gap junction proteins, connexin 30 (Cx30) and connexin 43 (Cx43), form networks that aid in K+ spatial buffering, cell volume regulation, and many other brain homeostatic functions.  The functions of connexins in the healthy and epileptic brain, their contribution to signal propagation, and the role they play in fast oscillation and seizure synchronization are all discussed in Chapter 11:  Gap junctions. 

The brain has many protective mechanisms to avoid insult by foreign pathogens.  The blood-brain barrier (BBB) is a multicellular interface between the central nervous system and the peripheral circulatory system.  It is comprised of several different cell types and structures, including astrocytic endfoot processes, endothelial cells, and pericytes.  Together, this tightly regulated structure allows the brain to form a unique micro-environment that is stable and independent from the rest of the body.  When the brain does suffer an insult, however, its immune response can minimize the damage done.  Divided into innate, adaptive, and complement components, the immune response uses a network of cells and signaling molecules (cytokines) that, together, elicit a variety of biological responses.   Perturbations in either of these, such as seen in the epileptic brain, can have serious consequences in network function.  An overview of BBB composition and evidence linking BBB disruption to epilepsy are presented in Chapter 12:  Blood-brain barrier disruption.  The pro-epileptogenic effects of neuroinflammation and activation of the immune response, such as increased cytokine production and leukocyte infiltration, are all discussed in Chapter 13:  Inflammation.

Current antiepileptic drugs (AEDs) available to patients today largely act by targeting neurons.  AEDs, however, are ineffective at controlling seizures in ~30% of patients and are associated with significant adverse effects such as impairment of cognition.  The numerous changes that occur in astrocytes in epilepsy has uncovered exciting new therapeutic targets for AED development.  What might be called “translational glioscience” was largely unexplored until recently but has now blown up into one of the most exciting fields in neuroscience.  Astrocyte-based therapeutic strategies are discussed in Chapter 14:  Therapeutic targets and future directions, and could also be applicable to many other neurological disorders, many of which are now considered “gliopathies”.

astrocytes and epilepsy

Astrocytes and Epilepsy summarizes the historical and current literature on the role of astrocytes in the development and maintenance of seizure activity.  Dramatic increases in our understanding of glioscience will hopefully translate into gliotherapies for not only the treatment of epilepsy, but also for other neurological disorders.  Identification of these gliopathic changes in combination with targeted treatment strategies could potentially protect the brain and prevent its conversion into the diseased state.

If you would like to purchase a print or e-copy of the book, visit the Elsevier Store. Apply discount code STC215 and receive 30% off the list price and free global shipping. If you would like to download additional chapters, you can access the book via ScienceDirect.

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