Models of Seizures and Epilepsy

Asla Pitkänen, Philip A. Schwartzkroin, Solomon L. Moshé

• Publisher: Academic Press
• Year: 2005
• Print ISBN: 9780120885541
• eBook ISBN: 9780080457024
• Topic: Psicologia
• Subtopic: Neurologia

An understanding of mechanisms underlying seizure disorders depends critically on the insights provided by model systems. In particular with the development of cellular, molecular, and genetic investigative tools, there has been an explosion of basic epilepsy research. Models of Seizures and Epilepsy brings together, for the first time in 30 years, an overview of the most widely-used models of seizures and epilepsy.Chapters cover a broad range of experimental approaches (from in vitro to whole animal preparations), a variety of epileptiform phenomenology (including burst discharges and seizures), and suggestions for model characterization and validation, such as electrographic, morphologic, pharmacologic, and behavioral features. Experts in the field provide not only technical reviews of these models but also conceptual critiques - commenting on the strengths and limitations of these models, their relationship to clinical phenomenology, and their value in developing a better understanding and treatments.Models of Seizures and Epilepsy is a valuable, practical reference for investigators who are searching for the most appropriate laboratory models for addressing key questions in the field. It also provides an important background for physicians, fellows, and students, offering insight into the potential for advances in epilepsy research.- The first comprehensive description of animal models of epilepsy since the early 1970's- Comprehensive analysis of "What the models model" to guide the selection of each model, and what specific questions it will answer- Elegant examples of the use of novel technologies that can be applied in experimental epilepsy research- World expert opinions on the clinical relevance of each model

CHAPTER 1 What Should Be Modeled?

JEROME. ENGEL, JR., PHILIP A. SCHWARTZKROIN

Epilepsy accounts for a significant portion of the disease burden worldwide (Murray and Lopez, 1994). The economic, social, and personal costs of this disorder are due largely to uncontrolled seizures (Begley et al., 2000), which underscores the need for more research into new approaches for the diagnosis, treatment, and prevention of epilepsy and its consequences. Although one could argue that research on human epilepsy ideally should be carried out on humans with epilepsy, this approach is not always possible or practical (Engel, 1998). Obvious ethical constraints exist, particularly those associated with the invasive techniques often needed to pursue important investigative questions. It is difficult to control for clinical variables, and control data can be impossible to obtain. Statistical analysis frequently requires larger populations than can be obtained from most clinical practices. Finally, the cost of carrying out research projects on patients would be prohibitive. Consequently, despite a tremendous increase in the opportunities for noninvasive research on the human brain provided by modern neuroimaging and growing access to direct investigations in the setting of epilepsy surgery, animal models of epilepsy and epileptic seizures are—and most likely will remain for the foreseeable future—essential to epilepsy research.

This book provides an update on the large variety of animal models available to neuroscientists interested in carrying out research on epilepsy. This introductory chapter reviews the various reasons why animal models might be used, what specifically can and should be modeled, and how these models might provide insight into questions of interest and concern (i.e., what can be measured).

WHY MODEL?

Animal models of epilepsy most often are used to investigate fundamental neuronal mechanisms of both abnormal(usually epilepsy related) and normal brain function. Animal models of epilepsy are also important, however, for research designed specifically to devise new diagnostic approaches or to test the efficacy of new antiepileptic drugs or other novel therapeutic interventions. It is likely that in the future animal models will be needed to test preventive (i.e., antiepileptogenic) measures as well.

Modeling to Understand Basic Mechanisms

Elucidation of the fundamental mechanisms of epilepsy and epilepsy-related phenomena is essential for devising new diagnostic, therapeutic, and preventative approaches to human epilepsy and its consequences. Until relatively recently, almost everything we knew, or thought we knew, about neuronal events underlying epileptic phenomena derived from research using animals. From the outset, however, the most pertinent questions that needed to be answered about epilepsy derived from observations of patients. Answers obtained in the animal laboratory required validation of clinical relevance, again by observing patients.

Although the use of animal models to understand the fundamental mechanisms of epilepsy and its consequences is the major theme of this volume, it is important to recognize that animal models of epilepsy, and of epileptic seizures, also have been used to elucidate neuronal mechanisms of normal brain function (Engel et al., 2001). For instance, the discrete perturbations induced by various epileptogenic insults have served as a valuable tool for mapping pathways and synaptically related regions in the brain, both anatomically (e.g., using histological 2-deoxyglucose [2DG] autoradiography and immediate early gene methodologies) and physiologically (e.g., with strychnine neuronography). Epileptic seizures have also been commonly used by physiological psychologists for a variety of investigational paradigms that require controlled interruption of behavior. Studies of oscillatory brain waves—a prominent feature of normal cerebral function—have been approached through the window of epileptiform phenomena. Our understanding of inhibitory control of brain excitability has been based largely on studies of epilepsy models. Perhaps most important is that modern investigations into brain “plasticity” mechanisms have a significant basis in studies of epileptogenesis.

Research using models of different aspects of epilepsy-and seizure-related phenomena provides different types of insights into basic mechanistic questions:

Acute seizure models: Studies of acute seizures in otherwise normal animals have made us aware of a host of potentially important cellular and molecular processes that might be involved in both the generation and the termination of epileptic seizure, and these possibilities remain the focus of much of today’s research (Avanzini et al., 1998; Engel, 1992; Purpura et al., 1972; Schwartzkroin, 1993). Early workers produced acute generalized epileptic seizures in animals using maximal electroshock and various chemoconvulsants (laboratory procedures that are still commonly used today) as well as a variety of other insults, such as insulin shock and trauma. Localized acute epileptic seizures were created by focal electrical stimulation and by local application of convulsant drugs such as strychnine and penicillin. Such techniques provoked acute ictal (i.e., seizure) activity in otherwise normal brains, permitting investigations of the fundamental neuronal basis of ictal discharge and seizure termination. These studies led to a number of hypotheses regarding the cellular bases of seizure activity, including alterations in intrinsic properties of neurons, loss of inhibition or increased excitatory synaptic activity, and changes in the extracellular milieu. This research also led to theories about seizure termination, such as energy depletion, desynchronization, depolarization block, and release of antiseizure substances like adenosine. Although it was often possible to determine why experimental interventions produced seizures, these manipulations were artificial and there was little or no way to relate these mechanisms of seizure initiation to those of spontaneous generation of seizures in patients. Acute seizures have also been useful, as indicated previously, as a perturbation for those interested in investigating normal brain function.

Chronic epilepsy models: Neuroscientists interested in understanding mechanisms of epilepsy have developed a number of chronic animal models with which to investigate persistent epileptogenic abnormalities present between seizures, or interictally. Chronic animal models have offered opportunities to investigate a large set of potentially important and clinically relevant mechanisms, including excitotoxicity and synaptic reorganization, altered voltage-gated channel functions, sprouting with synaptic reorganization, the development of novel receptors and receptor complements, and astrocyte activation. Many chronic epilepsy models were created specifically to reproduce particular types of human epilepsy, particularly the most common form, mesial temporal lobe epilepsy (MTLE) (Wieser et al., 2004). Seizures in MTLE originate in mesial temporal limbic structures, particularly the hippocampus and adjacent parahippocampal cortex. Most patients with MTLE have ...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Dedication
• Contributing Authors
• Foreword
• Preface
• Chapter 1: What Should Be Modeled?
• A.: IN VITRO PREPARATIONS
• B.: INDUCED SEIZURES IN INTACT ANIMALS
• C.: GENETIC MODELS
• D.: ACQUIRED FOCAL MODELS
• E.: MODELS USED FOR PHARMACOLOGICAL ASSESSMENT
• F.: TECHNICAL APPROACHES FOR MODEL CHARACTERIZATION
• G.: IMPORTANT QUESTIONS
• Index