Models of Seizures and Epilepsy

1104 Pages·2017·83.604 MB·English

by  Asla Pitkänen, Paul Buckmaster, Aristea S Galanopoulou and Solomon L. Moshé (Eds.)

Models of Seizures
and Epilepsy
Second edition
Edited by
Asla Pitkänen
A.I. Virtanen Institute
University of Eastern Finland
Kuopio, Finland
Paul S. Buckmaster
Stanford University
Stanford, CA, United States
Aristea S. Galanopoulou
Albert Einstein College of Medicine
Bronx, NY, United States
Solomon L. Moshé
Albert Einstein College of Medicine
Bronx, NY, United States
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Contributors
Isamu Aiba, Baylor College of Medicine, Houston, TX, Gordon Buchanan, University of Iowa, Iowa City, IA,
United States United States
Pedro Andrade, A.I. Virtanen Institute for Molecular Paul S. Buckmaster, Stanford University, Stanford, CA,
Sciences, University of Eastern Finland, Kuopio, United States
Finland
Guilhem Calas, Armed Forces Biomedical Research
Eskedar A. Angamo, Neuroscience Research Center, Institute, Brétigny sur Orge, France
Charite Medical University, Berlin, Germany
Peter L. Carlen, Krembil Research Institute, Toronto
Eleonora Aronica, Academic Medical Center, Western Hospital, University Health Network;
University of Amsterdam, Amsterdam; Foundation University of Toronto, Toronto, ON, Canada
Epilepsy Institutes Netherlands (SEIN),
Lionel Carmant, Montreal University and CHU Sainte-
The Netherlands
Justine Research Centre, Montreal, QC, Canada
Stéphane Auvin, INSERM, Robert Debré Children
Carlos Cepeda, Intellectual and Developmental
Hospital, Paris, France
Disabilities Research Center, Semel Institute for
Richard A. Baines, University of Manchester, Neuroscience and Human Behavior, UCLA School of
Manchester, United Kingdom Medicine, Los Angeles, CA, United States
Silvia Balosso, Institute for Pharmacological Research Frances S. Cho, Gladstone Institute for Neurological
Mario Negri, Milano, Italy Disease; University of California San Francisco,
Melissa Barker-Haliski, University of Washington, San Francisco, CA, United States
Seattle, WA, United States Alexandra Clemente, Gladstone Institute for
Fabrice Bartolomei, INSERM–National Institute Neurological Disease; University of California
of Health and Medical Research; Aix Marseille San Francisco, San Francisco, CA, United States
University, Marseille, France James C. Cloyd, University of Minnesota, Minneapolis,
Jeffrey Bastar, University of Utah School of Medicine, MN, United States
Salt Lake City, UT, United States Francesca Colciaghi, Molecular Neuroanatomy and
Giorgio Battaglia, Molecular Neuroanatomy and Pathogenesis Unit, IRCCS Foundation Neurological
Pathogenesis Unit, IRCCS Foundation Neurological Institute “C. Besta”, Milano, Italy
Institute “C. Besta”, Milano, Italy Lisa D. Coles, University of Minnesota, Minneapolis,
Tim Benke, University of Colorado, Denver, CO, United MN, United States
States Valerio Conti, A Meyer Children’s Hospital, University
Yevgeny Berdichevsky, Lehigh University, Bethlehem, of Florence, Florence, Italy
PA, United States Daniëlle Copmans, KU Leuven, Leuven, Belgium
Christophe Bernard, Aix Marseille University, Inserm,
Douglas A. Coulter, University of Pennsylvania Perelman
INS, Institute of Neurosciences of Systems, Marseille,
School of Medicine and the Research Institute at
France
the Children’s Hospital of Philadelphia, Abramson
Daniele Bertoglio, Molecular Imaging Center Antwerp Pediatric Research Center, Philadelphia, PA, United
(MICA), University of Antwerp, Antwerp, Belgium States
Edward H. Bertram, University of Virginia Health Gregory Dal Bo, Armed Forces Biomedical Research
Sciences Center, Charlottesville, VA, United States Institute, Brétigny sur Orge, France
xvii
xviii Contributors
Louis T. Dang, University of Michigan, Ann Arbor, MI, Alon Friedman, Zlotowski Center for Neuroscience, Ben-
United States Gurion University of the Negev, Beer-Sheva, Israel;
Marco de Curtis, The Foundation of the Carlo Besta Dalhousie University, Halifax, NS, Canada
Neurological Institute, Milano, Italy Siegrun Gabriel, Neuroscience Research Center, Charite
Peter A.M. de Witte, KU Leuven, Leuven, Belgium Medical University, Berlin, Germany
Stefanie Dedeurwaerdere, University of Antwerp, Aristea S. Galanopoulou, Albert Einstein College of
Antwerp, Belgium Medicine, Bronx, NY, United States
Steven Deleye, Molecular Imaging Center Antwerp Carlo N.G. Giachello, University of Manchester,
(MICA), University of Antwerp, Antwerp, Belgium Manchester, United Kingdom
Nora Dengler, Charite Medical University, Berlin, Joseph Glykys, Massachusetts General Hospital and
Germany Harvard Medical School, Boston, MA, United States
Antoine Depaulis, INSERM––National Institute of Health Vadym Gnatkovsky, The Foundation of the Carlo Besta
and Medical Research, U1216 -Grenoble Institute Neurological Institute, Milano, Italy
of Neuroscience; University of Grenoble, Grenoble Alica M. Goldman, Baylor College of Medicine,
Institute of Neurosciences; University Hospital of Houston, TX, United States
Grenoble, Grenoble, France Jeffrey Goodman, State University of New York
Colin Deransart, INSERM––National Institute of Health Downstate Medical Center; The Institute for
and Medical Research, U1216 -Grenoble Institute Basic Research in Developmental Disabilities,
of Neuroscience; University of Grenoble, Grenoble NY, United States
Institute of Neurosciences; University Hospital of Jan A. Gorter, Center for Neuroscience, Swammerdam
Grenoble, Grenoble, France Institute for Life Sciences, University of Amsterdam,
Frederic Dorandeu, Armed Forces Biomedical Research Amsterdam, The Netherlands
Institute, Brétigny sur Orge; Ecole du Val-de-Grâce, Olli Gröhn, A.I. Virtanen Institute, University of Eastern
Paris, France Finland, Kuopio, Finland
F. Edward Dudek, University of Utah School of Renzo Guerrini, A Meyer Children’s Hospital, University
Medicine, Salt Lake City, UT, United States of Florence, Florence, Italy
Chris G. Dulla, Tufts University, Boston, MA, United Isabelle Guillemain, INSERM––National Institute of
States Health and Medical Research, U1216–Grenoble
Volodya Dzhala, Massachusetts General Hospital and Institute of Neuroscience; University of Grenoble,
Harvard Medical School, Boston, MA, United States Grenoble Institute of Neurosciences,
Jeffrey Ekstrand, University of Utah School of Medicine, Grenoble, France
Salt Lake City, UT, United States Peter Halasz, Pázmány Péter Catholic University,
Ana M. Estrada-Sánchez, Intellectual and Developmental Budapest, Hungary
Disabilities Research Center, Semel Institute for Uwe Heinemann, Neuroscience Research Center, Charite
Neuroscience and Human Behavior, UCLA School of Medical University, Berlin, Germany
Medicine, Los Angeles, CA, United States David C. Henshall, Royal College of Surgeons in Ireland,
James H. Eubanks, Krembil Research Institute, Dublin, Ireland
University Health Network, Toronto, ON, Canada Stephanie Holden, Gladstone Institute for Neurological
Carl Faingold, Southern Illinois University School of Disease; University of California San Francisco, San
Medicine, Springfield, IL, United States Francisco, CA, United States
Raafat Fares, Armed Forces Biomedical Research Gregory L. Holmes, University of Vermont, Burlington,
Institute, Brétigny sur Orge, France VT, United States
R.J. Ferland, Albany Medical College, Albany, NY, Chris Hovens, Royal Melbourne Hospital, the University
United States of Melbourne, Melbourne, VIC, Australia
T.N. Ferraro, Cooper Medical School of Rowan Anton I. Ivanov, Aix Marseille University, Inserm,
University, Camden, NJ, United States INS, Institute of Neurosciences of Systems,
Adele Finardi, Molecular Neuroanatomy and Marseille, France
Pathogenesis Unit, IRCCS Foundation Neurological Laura A. Jansen, University of Virginia, Charlottesville,
Institute “C. Besta”, Milano, Italy VA, United States
Contributors xix
Guillaume Jarre, INSERM––National Institute of Health Jenni Kyyriäinen, A.I. Virtanen Institute for Molecular
and Medical Research, U1216–Grenoble Institute Sciences, University of Eastern Finland, Kuopio, Finland
of Neuroscience; University of Grenoble, Grenoble
Wolfgang Löscher, University of Veterinary Medicine
Institute of Neurosciences, Grenoble, France
Hannover, and Center for Systems Neuroscience,
Paul R. Jarvis, University of Vermont, Burlington, VT, Hannover, Germany
United States Lauren A. Lau, Tufts University, Boston, MA, United
John G.R. Jefferys, University of Oxford, Oxford, United States
Kingdom Thomas-Nicolas Lehmann, Neurosurgery Clinic,
Frances E. Jensen, Perelman School of Medicine, University HELIOS Clinic, Bad Saarow, Germany
of Pennsylvania, Philadelphia, PA, United States Ilo E. Leppik, University of Minnesota, Minneapolis,
Anna Jeong, Washington University School of Medicine, MN, United States
St. Louis, MO, United States Michael S. Levine, Intellectual and Developmental
Xiaoming Jin, Spinal Cord and Brain Injury Research Disabilities Research Center, Semel Institute for
Group, Stark Neurosciences Research Institute, Indiana Neuroscience and Human Behavior, UCLA School of
University School of Medicine, Indianapolis, IN, Medicine, Los Angeles, CA, United States
United States Laura Librizzi, The Foundation of the Carlo Besta
Yishi Jin, Howard Hughes Medical Institute, University of Neurological Institute, Milano, Italy
California San Diego, La Jolla, CA, United States Kyle Lillis, Massachusetts General Hospital and Harvard
Rüdiger Köhling, Oscar-Langendorff-Institute of Medical School, Boston, MA, United States
Physiology, Rostock University Medical Centre, Dean D. Lin, McKnight Brain Institute, University of
Rostock, Germany Florida, Gainesville, FL, United States
Shilpa D. Kadam, Hugo Moser Research Institute at Wei-Hsiang Lin, University of Manchester, Manchester,
Kennedy Krieger & Department of Neurology, Johns United Kingdom
Hopkins University School of Medicine, Baltimore,
Angelika Mühlebner, Academic Medical Center,
MD, United States
University of Amsterdam, Amsterdam,
Daniela Kaufer, Helen Wills Neuroscience Institute, The Netherlands
University of California, Berkeley, CA, United States
Nicola Marchi, Cerebrovascular Mechanisms of
Kevin M. Kelly, Drexel University College of Medicine, Brain Disorders, Institute of Functional Genomics
Philadelphia; Carnegie Mellon University, Pittsburgh; (CNRS-INSERM), Montpelier, France
Allegheny Health Network Research Institute,
Andrey M. Mazarati, Department of Pediatrics, David
Allegheny General Hospital, Pittsburgh, PA,
Geffen School of Medicine at UCLA, Los Angeles,
United States
CA, United States
Mary E. Kelly, Children’s Hospital of Philadelphia,
Dan Z. Milikovsky, Zlotowski Center for Neuroscience,
Abramson Pediatric Research Center, Philadelphia,
Ben-Gurion University of the Negev, Beer-Sheva,
PA, United States
Israel
Andrea Klang, Institute of Pathology and Forensic Julien Modolo, INSERM–National Institute of Health
Veterinary Medicine, University of Veterinary and Medical Research; University of Rennes, Rennes,
Medicine, Vienna, Austria France
Henrik Klitgaard, UCB Biopharma SPRL, Brussels, Solomon L. Moshé, Albert Einstein College of Medicine,
Belgium Bronx, NY, United States
Sibylle Kneissl, Diagnostic Imaging, University of Prosper N’Gouemo, Georgetown University Medical
Veterinary Medicine, Vienna, Austria Center, Washington, DC, United States
George K. Kostopoulos, University of Patras, Patras, Xavier Ekolle Ndode-Ekane, A.I. Virtanen Institute for
Greece Molecular Sciences, University of Eastern Finland,
Robert J. Kotloski, University of Wisconsin; William S. Kuopio, Finland
Middleton Memorial Veterans Hospital, Madison, WI, Astrid Nehlig, INSERM, Necker Hospital, Paris,
United States France
Marie Kuker, Kuker Regulatory Consulting, LLC, Jamila Newton, Georgetown University Medical Center,
Mahtomedi, MN, United States Washington, DC, United States
xx Contributors
Paola Nobili, Molecular Neuroanatomy and Pathogenesis Felipe S. Salinas, University of Texas Health Science
Unit, IRCCS Foundation Neurological Institute Center at San Antonio, San Antonio, TX, United
“C. Besta”, Milano, Italy; Paris Descartes University, States
Paris, France
Nathalie T. Sanon, CHU Sainte-Justine Research Centre,
Jeffrey L. Noebels, Baylor College of Medicine, Houston, Montreal, QC, Canada
TX, United States
Michael P. Shakarjian, New York Medical College,
Terence J. O’Brien, Royal Melbourne Hospital, the Valhalla, NY, United States
University of Melbourne, Melbourne, VIC, Australia
Tarek Shaker, Montreal University and CHU Sainte-
Heather O’Leary, University of Colorado, Denver, CO, Justine Research Centre, Montreal, QC, Canada
United States
Sandy Shultz, Royal Melbourne Hospital, the University
Akos Pakozdy, Clinic for Internal Medicine and of Melbourne, Melbourne, VIC, Australia
Infectious Disease, University of Veterinary Medicine,
Aleksandra Siekierska, KU Leuven, Leuven, Belgium
Vienna, Austria
Ivan Soltesz, Stanford University, Stanford, CA, United
Jack M. Parent, University of Michigan and VA Ann
States
Arbor Healthcare System, Ann Arbor, MI, United States
Jay G. Spampanato, University of Utah School of
Lotta Pasanen, A.I. Virtanen Institute for Molecular
Medicine, Salt Lake City, UT, United States
Sciences, University of Eastern Finland, Kuopio, Finland
Kevin J. Staley, Massachusetts General Hospital, Harvard
Dipan C. Patel, University of Utah, Salt Lake City, UT,
Medical School, Boston, MA, United States
United States
Mark Stewart, State University of New York Downstate
Edward N. Patterson, University of Minnesota, St. Paul,
Medical Center, NY, United States
MN, United States
Hongyu Sun, Carleton University, Ottawa, ON, Canada
Jeanne T. Paz, Gladstone Institute for Neurological
Disease; University of California San Francisco, San Thomas P. Sutula, University of Wisconsin, Madison, WI,
Francisco, CA, United States United States
Steve Petrou, The Florey Institute of Neuroscience and Charles Á. Szabó, University of Texas Health Science
Mental Health; Royal Melbourne Hospital, Melbourne, Center at San Antonio, San Antonio, TX, United
VIC, Australia States
Xingjie Ping, Spinal Cord and Brain Injury Research Seika Takayanagi-Kiya, University of California San
Group, Stark Neurosciences Research Institute, Diego, La Jolla, CA, United States
Indiana University School of Medicine, Indianapolis, Heikki Tanila, A.I. Virtanen Institute for Molecular
IN, United States Sciences, University of Eastern Finland, Kuopio,
Asla Pitkänen, A.I.Virtanen Institute for Molecular Finland
Sciences, University of Eastern Finland, Kuopio,
Jerrold Tannenbaum, University of California Davis,
Finland
Davis, CA, United States
Heidrun Potschka, Institute of Pharmacology,
Srinivasan Tupal, Southern Illinois University School of
Toxicology, and Pharmacy, Ludwig-Maximilians-
Medicine, Springfield, IL, United States
University, Munich, Germany
Laura Uva, The Foundation of the Carlo Besta
Ivan Raikov, Stanford University, Stanford, CA, United
Neurological Institute, Milano, Italy
States
Erwin A. van Vliet, Academic Medical Center, University
Teresa Ravizza, Institute for Pharmacological Research
of Amsterdam, Amsterdam, The Netherlands
Mario Negri, Milano, Italy
Libor Velíšek, New York Medical College, Valhalla, NY,
Doodipala S. Reddy, Texas A&M Health Science Center, United States
Bryan, TX, United States
Jana Velíšková, New York Medical College, Valhalla,
Kay L. Richards, The Florey Institute of Neuroscience NY, United States
and Mental Health, Melbourne, VIC, Australia
Matthew C. Walker, Institute of Neurology, University
Steven N. Roper, McKnight Brain Institute, University of College London, London, United Kingdom
Florida, Gainesville, FL, United States
Fabrice Wendling, INSERM–National Institute of Health
Seda Salar, Neuroscience Research Center, Charite and Medical Research; University of Rennes, Rennes,
Medical University, Berlin, Germany France
Contributors xxi
H. Steve White, University of Washington, Seattle, WA, Andrew Zayachkivsky, Neurona Therapeutics, San
United States Francisco, CA, United States
Karen S. Wilcox, University of Utah, Salt Lake City, Liang Zhang, Krembil Research Institute, Toronto
UT, United States Western Hospital, University Health Network;
Michael Wong, Washington University School of University of Toronto, Toronto, ON, Canada
Medicine, St. Louis, MO, United States Ping Zheng, Royal Melbourne Hospital, the University of
Robert C. Wykes, Institute of Neurology, University Melbourne, Melbourne, VIC, Australia
College London, London, United Kingdom
Foreword
The year 2006 saw the publication of Models of Seizures on animal models? Can we rely on models based on low-
and Epilepsy, edited by Pitkänen, Schwartzkroin, and er animal species (or in vitro) to provide critical insights?
Moshé (Pitkänen et al., 2006). It had been 34 years since Hopefully, this volume will give the reader a sense why it is
the previous effort to summarize the state of experimental important to continue developing animal models to achieve
epilepsy research, as presented in the 1972 volume edited advances in biomedical sciences.
by Purpura, Penry, Tower, Woodbury, and Walter, Experi- Relevant to this ethical question, a striking feature of the
mental Models of Epilepsy—A Manual for the Laboratory modern approach to epilepsy research is our ambivalence
Worker (Purpura et al., 1972). Now, only 10 years after the toward “simplification” in the laboratory. Experiments, by
volume by Pitkänen et al. (2006), we have a second edition their very nature, allow us to simplify the natural complexity
of Models. What justifies this “quick” update? Are there so of epilepsy conditions - controlling variables, working often
many new models? Has laboratory work progressed to a in a single animal species with uniform genetics, studying
new level? Indeed, is our thinking about epilepsy (and sei- the brains of animal species that are much less complex
zures) so much different now than it was 10 years ago? The than the human brain, or using small pieces of brain tissue
answer to all these questions is “yes.” in artificial (defined) environments. While this drive toward
As the reader will see clearly by even a cursory glance simplification offers the researcher powerful experimental
through the Table of Contents of this new Models volume, tools, our modern research approaches now also incorporate
the numbers of models has increased steadily. But, more more realistic complexities - for example, acknowledging
importantly, our progress is reflected in how we are using the importance of varying genetic backgrounds, the influ-
these models. Again, a look at the Table of Contents shows ence of fluctuating biological (e.g., hormonal) systems, the
that we are very much concerned not only with the model occurrence of epilepsies in complex mammalian species
itself, but also with our approach to studying these animal other than the human. Perhaps, most notably, we are now
models. While such issues as research ethics and laboratory keenly aware of the fact that epilepsy is more than “just
practice have always been a feature of laboratory experi- seizures”; our research on animal models reflects a rela-
mentation, we now confront “trade-offs” and limitations of tively new preoccupation with defining, understanding, and
this type of research in an explicit manner, identifying what treating these additional features - that is, comorbidities, of
we can and can’t do in the laboratory. epilepsy.
When we talk about a “model,” we are generally refer- The nature of our models, and how we apply them to
ring to a nonhuman system, usually another animal species, clinically important conditions, depends critically on cur-
in which we can create something similar to a phenomenon rent experimental (and clinical) technology. Indeed, one
of interest in people (e.g., a particular form of epilepsy). But could argue that the questions we ask and the models we
we need to ask, and answer, why our research should focus develop are directly driven by new technologies. Epilepsy
so intensely on animal models. This question is particularly model development started with a focus on behavioral sei-
important in light of recent efforts in Europe to eliminate zure phenomenology, but took a major step forward when
most animal research [see the ILAE/AES response to the researchers (and clinicians) began to use EEG monitoring as
European Citizens “Stop Vivisection” Initiative (ILAE/ a basis for determining whether an animal (or a patient) had
AES, 2015), debated in the European Parliament]. While an epileptic seizure. Our understanding of the mechanisms
most people agree that it is unethical to carry out experi- underlying seizure-like activities took another step forward
ments on other human beings, the case for animal model as more sophisticated electrophysiological techniques were
experimentation is far from settled. For example, we now applied (single cell recordings, etc.). Similarly, advances
have rather sophisticated computer modeling capabilities in imaging technology have had a tremendous impact, cer-
that theoretically enable us to recreate potential epileptic tainly at the experimental level, but perhaps even more so
brain circuits and networks, and epileptic neurons, in the in the clinic. These technical advances have given investi-
virtual world. Can computer modeling replace experiments gators new tools for investigating the models that already
xxiii
xxiv Foreword
are in use, and have allowed them to approach models that among the targets of our epilepsy models - for example,
had previously been viewed as “black boxes.” Technical ad- whether there are common underlying neuropathologies,
vances have also led to novel approaches to stopping and/or or shared genetic predispositions. At the same time, we are
reducing seizure activity - for example, focal application of now acutely aware of comorbidities, such as depression,
drugs, deep brain stimulation, or cell transplantation. With- cognitive delay, etc., that are associated with seizure dis-
out the introduction of such innovative techniques, labora- orders themselves. Model development and application of
tory studies using animal (and “reduced”) models would new experimental tools are providing important new un-
soon be at a standstill. Novel technical advances have also derstanding of seizure comorbidities - how these additional
led to new experimental insights regarding the “cause” (or burdens develop, how they are related to seizure generation,
at least the initiation) of epilepsy (or seizures) in an organ- and how they can be addressed in our attempts to develop
ism, as seen dramatically with our advancing understanding new therapeutic strategies.
of how genetic variability may be involved in epilepsies (or The strong message from both clinical and experimen-
seizure propensity). When Models by Pitkänen, Schwartz- tal/model studies is that epilepsy cannot be considered, or
kroin, and Moshé was published in 2006, seizure models studied, as a unitary disorder. Each different disease must
based on manipulation of an animal’s genetics appeared to be understood within the framework of the organism’s age,
be the wave of the future. That promise has certainly been the state of brain development, the causal features of the
realized. Not only have we seen an explosion in the number epilepsy, etc. As we consider the important interactive feed-
of genetic models (mostly in mouse), but also unexpected back loops between the bench and the bedside, between ex-
application of new genetic/molecular techniques (e.g., cell perimental models and the human disorders that we hope to
transplantation, optogenetics) for inducing (or reducing) ab- cure, it is clear that epilepsy research is truly “translational.”
normal electrical activities. Many of these new techniques Experimental modeling certainly does provide an incredibly
are highlighted in this new Models volume. powerful tool for addressing important research and clinical
Just as technical advances have driven new investiga- questions. However, it remains the case that it is the ques-
tions with epilepsy/seizure models, so too has the clinical tions we ask of these models that are the keys to progress.
identification of different forms of epilepsy and epilepsy Models give us an opportunity to refine our questions, and to
syndromes been critical for recent model studies. The iden- enter into a dialogue that moves the field forward.
tification of genetic epilepsies has been at the forefront of
this effort. So, too, have our investigations of clinical phe- Philip A. Schwartzkroin, PhD
nomenologies - the many facets of a seizure or epilepsy dis- Davis, CA, United States
order (etiology, clinical expression, electrical brain activity,
localization, etc.). Finally, the clinical awareness of the age-
dependencies of various seizure types has now grown into a REFERENCES
major feature of epilepsy modeling. Animal models provide
an indispensable window through which to view, and gain ILAE/AES, 2015. Request to oppose the European Citizen’s Initiative
further insight into, these factors. “Stop Vivisection”, Open letter. Available from: http://www.ilae.org/
Visitors/News/documents/Letter-to-MEPsILAEIBEweb.pdf
There is growing awareness of seizures as a feature of
Pitkänen, A., Schwartzkroin, P.A., Moshé, S.L. (Eds.), 2006. Models of
numerous neurological disorders (e.g., Alzheimer’s dis-
Seizures and Epilepsy. Elsevier/Academic Press, Amsterdam, The
ease), and laboratory investigators are using our newly de-
Netherlands.
veloped tools to try to understand why seizures appear in
Purpura, D.P., Penry, J.K., Tower, D.B., Woodbury, D.M., Walter, R.D.
these disparate disorders. There is a new appreciation of
(Eds.), 1972. Experimental Models of Epilepsy—A Manual for the
what might we learn by including these “related” disorders Laboratory Worker. Raven Press, New York, NY.
Preface
The ultimate motivation behind the creation and use of as numerous new models of epilepsies of genetic origin),
animal models of seizures and epilepsy is the wish to un- seizures of metabolic etiology, or sudden unexpected death
derstand the pathogenic mechanisms, and develop new in epilepsy (SUDEP). Further, the community has become
therapies for seizures and epilepsies. As the field of animal increasingly aware of the occurrence of epilepsy in models
modeling of seizures keeps growing, the scope, principles, that are used to investigate other neurological diseases.
and methodologies evolve and adapt to the new technologi- Therefore, we have also added chapters describing the epi-
cal advances, research priorities, and ethical and method- lepsy phenotype, for example, in neurodegenerative diseas-
ological challenges. es, autism, Rett syndrome, depression, inflammation, and
The early stages of animal modeling were marked by infections.
the excitement of exploring new ways to model seizures Over these past years, biomedical researchers have
and epilepsies in systems with various degrees of complex- been placing increasing care on ensuring the humane
ity, and ultimately in live organisms. This excitement was handling and justified use of animals. More stringent regu-
often curbed by the frustration of selecting among increas- latory requirements have called for the justification, refine-
ingly diverse approaches or incompletely described meth- ment, and optimization of experimental procedures used
odologies. In 1972, the first attempt to provide a manual in animal studies, in a manner that balances rigorous, sta-
and technical guide of the existing models of epilepsy was tistically powered science and ethics. Special chapters are
realized by Purpura, Penry, Tower, Woodbury, and Walter included discussing good laboratory practices, and ethical
(Experimental Models of Epilepsy—A Manual for the Labo- and regulatory aspects of animal research. Throughout the
ratory Worker, Raven Press, New York). This volume has text, chapters emphasize the translational value of existing
since played an influential role in fueling the explosion of animal models for the human seizures and epilepsy syn-
new animal models that followed. The wealth of animal dromes, as recognized in the newly proposed classifica-
models that ensued made it necessary to provide updates tion of the International League Against Epilepsy. Special
that could also serve as an intellectual guidance for animal chapters are also dedicated to naturally occurring epilep-
model selection. sies in animals, and the relevance of preclinical epilepsy
In 2006, Pitkänen, Schwartzkroin, and Moshé, edited research.
Models of Seizures and Epilepsy, geared to present the pur- We have enlisted in this project the assistance of a large
pose, limitations, clinical relevance, and factors that influ- group of investigators, selected by their personal contribu-
ence the phenotype of each model. Models were classified tions and expertise on the specific topics they are invited to
based on whether they recapitulated epileptiform activity, discuss. We have requested the authors to provide a clear
seizures, epileptogenesis, and epilepsies. This first edition and comprehensive description of the methodology and
has since served as an essential resource for epilepsy in- phenotype of each model. The defining features and charac-
vestigators using animal models that helped bring the focus teristics of each model are discussed, including age and sex-
upon translational research. related issues, seizure, and epilepsy phenotype (behavioral
The decision to produce a second edition of the Models and electrophysiological characterization), neuropathology,
book was taken to provide an update, and to incorporate imaging, comorbidities, diagnostic testing, species-, strain-,
the new directions and priorities in epilepsy research. Since and genetic background-related variations. The response to
2006, many new models of epilepsy have been developed. antiepileptic drugs is included, when known. The authors
These include the models of early life epilepsies (infan- also discuss how each model can be used for biomarker
tile spasms and other epileptic encephalopathies, as well and therapy development, including limitations, as well as
xxv