Microglia in Health and Disease

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Marie-Ève Tremblay • Amanda Sierra
Editors

Microglia in Health
and Disease
Editors
Marie-Ève Tremblay Amanda Sierra
Axe Neurosciences, Centre de recherche du Achucarro Basque Center for Neuroscience
CHU de Québec, and Department of University of the Basque Country
Molecular Medicine EHU/UPV
Université Laval Ikerbasque Foundation
Québec, QC, Canada Zamudio, Bizkaia, Spain

ISBN 978-1-4939-1428-9 ISBN 978-1-4939-1429-6 (eBook)

DOI 10.1007/978-1-4939-1429-6
Springer New York Heidelberg Dordrecht London

Library of Congress Control Number: 2014949136

© Springer Science+Business Media New York 2014

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To our families
Preface

These past few years have witnessed a revolution in our understanding of microglial
cells, since their roles in the healthy central nervous system have just started to be
revealed. These resident macrophages were shown to actively contribute to main-
taining health, in cooperation with neurons, glial cells, and other types of immune
cells, throughout the life-span, prompting reinterpretation of their long known
involvement with diseases.
To share with the broader scientific community the recent discoveries on some of
the most relevant topics in microglia research, from a diverse perspective, we pro-
pose a collection of 19 chapters from 52 specialists, working in 11 countries
(Australia, Canada, Chile, China, France, Germany, Japan, Spain, Switzerland, the
UK, and the USA) across 5 continents (Asia, Australia, Europe, North America,
South America), and presently at the graduate, postdoctoral, assistant, associate, or
full professor stages of their career.
To set microglia on the stage, we begin by explaining briefly who they are and
what they do: their origin, history, physiology, and immune functions, the recent
development of noninvasive methodologies to study microglia, and the ongoing
controversy about their neurotoxic versus neuroprotective implication in disease.
In the first section, we describe in more detail their physiological roles in the
maturation, function, and plasticity of the central nervous system, across normal
development, adolescence, adulthood, and aging. Doing so, we also address their
crucial involvement in neuropathic pain and drug addiction.
In the second section, we discuss their implication in pathologies impacting on
the quality of life: neurodevelopmental and neuropsychiatric disorders, AIDS, and
multiple sclerosis; and their contribution to leading causes of death: ischemia and
stroke, neurodegenerative diseases, as well as trauma and injury.
The chapters strictly discriminate between experimental data, hypotheses, and
speculations, so that the open questions are presented clearly to newcomers in this
young and vibrating field. Outdated terminologies such as “resting” and “activated”
microglial cells are replaced by a more thorough description of their actual pheno-
type, comprising concerted changes in morphology, gene expression, and functions.
The distinction between in vivo and in vitro data is also emphasized throughout the

vii
viii Preface

book, considering the importance of studying microglia in their normally prevailing

behavior, without inadvertently causing their reactive transformation during experi-
mental procedures. Contextual differences between central nervous system regions
and stages of the lifespan are also covered, whenever data is available.
As a result of this book, hopefully engaging the scientific community in a lively
discussion about microglial involvement in many more contexts of health and dis-
ease, we can envision an explosion of discoveries that will translate into the devel-
opment of better targeted and more efficient therapies in the near future.
We are particularly grateful to our editors at Springer, Simina Calin and Gina
Kahn, all the collaborators, our institutions and lab members, and most of all, our
families for supporting this grand endeavor.

Québec, QC, Canada Marie-Ève Tremblay

Zamudio, Bizkaia, Spain Amanda Sierra
Contents

Part I The General Setting

1 Introduction ............................................................................................. 3
Amanda Sierra and Marie-Ève Tremblay
2 Historical Context ................................................................................... 7
Payam Rezaie and Uwe-Karsten Hanisch
3 Microglial Physiology ............................................................................. 47
Jyoti J. Watters and Jennifer M. Pocock
4 Lessons from In Vivo Imaging ............................................................... 81
Dimitrios Davalos and Martin Fuhrmann
5 Roles in Immune Responses ................................................................... 115
Richa Hanamsagar, Sandra M. Cardona, Tammy Kielian,
and Astrid E. Cardona
6 Neuroprotection Versus Neurotoxicity .................................................. 145
Knut Biber and Michelle L. Block

Part II What Is on Stage

The New Roles

7 Developmental Neuronal Elimination ................................................... 175

José L. Marín-Teva, Julio Navascués, Ana Sierra,
and Michel Mallat
8 Developmental Vascularization, Neurogenesis, Myelination,
and Astrogliogenesis ............................................................................... 193
G. Jean Harry and Lorena Pont-Lezica

ix
x Contents

9 Developing and Mature Synapses .......................................................... 223

Marie-Ève Tremblay, Rosa C. Paolicelli, Beth Stevens,
Hiroaki Wake, and Alain Bessis
10 Adult Neurogenesis, Learning and Memory ........................................ 249
Amanda Sierra and Marie-Ève Tremblay
11 Neuropathic Pain..................................................................................... 273
Jessica K. Alexander, Simon Beggs, and Michael W. Salter
12 Drug Addiction ........................................................................................ 299
Xiaohui Wang, Thomas A. Cochran, Mark R. Hutchinson,
Hang Yin, and Linda R. Watkins
13 Aging ........................................................................................................ 319
Rommy von Bernhardi, Betsi Flores, and Hiroshi Nakanishi

Part III Their Pathological Implications

Conditions Impacting on the Quality of Life

14 Neurodevelopmental and Neuropsychiatric Disorders........................ 345

Akira Monji, Izumi Maezawa, Yoshito Mizoguchi,
Takahiro A. Kato, and Lee-Way Jin
15 Human Immunodeficiency Virus ........................................................... 373
Daniel F. Marker, Shao-Ming Lu, and Harris A. Gelbard
16 Multiple Sclerosis .................................................................................... 393
Yoshifumi Sonobe and Akio Suzumura

Leading Causes of Death

17 Ischemia and Stroke................................................................................ 413

Raffaela Cipriani, Maria Domercq, and Carlos Matute
18 Neurodegenerative Diseases ................................................................... 437
Diego Gomez-Nicola and V. Hugh Perry
19 Spinal Cord and Brain Trauma ............................................................. 455
Samuel David and Phillip G. Popovich

Index ................................................................................................................. 473

Contributors

Jessica K. Alexander, Ph.D. Program in Neurosciences and Mental Health,

Hospital for Sick Children, Toronto, ON, Canada
Simon Beggs, Ph.D. Program in Neurosciences and Mental Health, Hospital for
Sick Children, Toronto, ON, Canada
Rommy von Bernhardi, M.D., Ph.D. Department of Neurology, School of
Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
Alain Bessis, Ph.D. Institut de Biologie de l’Ecole Normale Supérieure, Inserm,
Paris, France
Knut Biber, Ph.D. Department of Psychiatry and Psychotherapy, Molecular
Psychiatry, University Hospital Freiburg, Freiburg, Germany
Department of Neurosciences, University Medical Center Groningen, The Netherlands
Michelle L. Block, Ph.D. Department of Anatomy and Neurobiology, Virginia
Commonwealth University, Richmond, VA, USA
Department of Anatomy & Cell Biology Indiana University School of Medicine
and The Stark Neuroscience Research Institute, Indianapolis, IN
Astrid E. Cardona, Ph.D. Department of Biology and South Texas Center for
Emerging Infectious Diseases, University of Texas at San Antonio, San Antonio,
TX, USA
Sandra M. Cardona, Ph.D. Department of Biology, University of Texas at San
Antonio, San Antonio, TX, USA
Raffaela Cipriani, Ph.D. Department of Neurosciences, CIBERNED and
Achucarro Basque Center for Neuroscience, University of Basque Country
EHU/UPV, Leioa, Spain
Thomas A. Cochran, B.A. Department of Psychology and the Center for
Neuroscience, University of Colorado at Boulder, Boulder, CO, USA

xi
xii Contributors

Dimitrios Davalos, Ph.D. Gladstone Institute of Neurological Disease, University

of California, San Francisco, San Francisco, CA, USA
Samuel David, Ph.D. Centre for Research in Neuroscience, The Research Institute
of the McGill University Health Center, Montreal, QC, Canada
María Domercq, Ph.D. Department of Neurosciences, CIBERNED and Achucarro
Basque Center for Neuroscience, University of Basque Country EHU/UPV,
Leioa, Spain
Betsi Flores Department of Biological Sciences, Universidad Andrés Bello,
Santiago, Chile
Martin Fuhrmann, Ph.D. Department of Neuroimmunology and Imaging,
German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
Harris A. Gelbard, M.D., Ph.D. Department of Neurology, Center for Neural
Development and Disease, University of Rochester Medical Center, Rochester,
NY, USA
Diego Gomez-Nicola, Ph.D. Centre for Biological Sciences, Southampton General
Hospital, University of Southampton, Southampton, UK
Richa Hanamsagar, B. Pharm., Ph.D. Department of Psychology and
Neuroscience, Duke University, Durham, NC, USA
Uwe-Karsten Hanisch, Ph.D. Institute of Neuropathology, University of
Göttingen, Göttingen, Germany
G. Jean Harry, Ph.D. National Toxicology Program Laboratory, National Institute
of Environmental Health Sciences/National Institutes of Health, Research Triangle
Park, NC, USA
Mark R. Hutchinson, Ph.D. Discipline of Physiology, School of Medical
Sciences, University of Adelaide, Adelaide, SA, Australia
Lee-Way Jin, M.D., Ph.D. Department of Pathology and Laboratory Medicine,
School of Medicine, University of California Davis Medical Center, Sacramento,
CA, USA
Takahiro A. Kato, M.D., Ph.D. Department of Neuropsychiatry, Graduate School
of Medical Sciences, Kyushu University, Fukuoka, Japan
Tammy Kielian, Ph.D. Departments of Pathology and Microbiology, University
of Nebraska Medical Center, Omaha, NE, USA
Shao-Ming Lu, Ph.D. Department of Neurology, Center for Neural Development
and Disease, University of Rochester Medical Center, Rochester, NY, USA
Izumi Maezawa, Ph.D. Department of Pathology and Laboratory Medicine,
School of Medicine, University of California Davis, M.I.N.D. Institute,
Sacramento, CA, USA
Contributors xiii

Michel Mallat, M.D., Ph.D. Institut du Cerveau et de la moelle épinière (ICM),

Hôpital de la Salpêtrière, Paris, France
José L. Marín-Teva, Ph.D. Departamento de Biología Celular, Universidad de
Granada, Granada, Spain
Daniel F. Marker, Ph.D. Department of Neurology, Center for Neural Development
and Disease, University of Rochester Medical Center, Rochester, NY, USA
Carlos Matute, Ph.D. Department of Neurosciences, CIBERNED and Achucarro
Basque Center for Neuroscience, University of Basque Country EHU/UPV,
Leioa, Spain
Yoshito Mizoguchi, M.D., Ph.D. Department of Psychiatry, Faculty of Medicine,
Saga University, Saga, Japan
Akira Monji, M.D., Ph.D. Department of Psychiatry, Faculty of Medicine, Saga
University, Saga, Japan
Hiroshi Nakanishi, Ph.D. Department of Aging Science and Pharmacology,
Faculty of Dental Sciences, Kyushu University, Fukuoka, Japan
Julio Navascués, Ph.D. Departamento de Biología Celular, Universidad de
Granada, Granada, Spain
Rosa C. Paolicelli, Ph.D. Division of Psychiatry Research, University of Zurich,
Schlieren, Switzerland
V. Hugh Perry, Ph.D. Centre for Biological Sciences, Southampton General
Hospital, University of Southampton, Southampton, UK
Jennifer M. Pocock, Ph.D. Department of Neuroinflammation, University College
London Institute of Neurology, London, UK
Lorena Pont-Lezica, Ph.D. Institut de Biologie de l’Ecole Normale Supérieure,
Inserm, Paris, France
Phillip G. Popovich, Ph.D. Department of Neuroscience, The Ohio State
University Wexner Medical Center, Center for Brain and Spinal Cord Repair,
Columbus, OH, USA
Payam Rezaie, Ph.D. Brain & Behavioural Sciences Discipline, Department of
Life, Health & Chemical Sciences, Faculty of Science, The Open University, Milton
Keynes, UK
Michael W. Salter, M.D., Ph.D. Program in Neurosciences and Mental Health,
Hospital for Sick Children, Toronto, ON, Canada
Department of Physiology, Faculty of Medicine, Centre for the Study of Pain,
University of Toronto, Toronto, ON, Canada
Amanda Sierra, Ph.D. Achucarro Basque Center for Neuroscience, University of
the Basque Country EHU/UPV, Ikerbasque Foundation, Zamudio, Bizkaia, Spain
xiv Contributors

Ana Sierra Departamento de Biología Celular, Universidad de Granada, Granada,

Spain
Yoshifumi Sonobe, Ph.D. Department of Neuroimmunology, Research Institute of
Environmental Medicine, Nagoya University, Nagoya, Japan
Beth Stevens, Ph.D. Department of Neurology, Harvard Medical School, Boston
Children’s Hospital, F.M. Kirby Neurobiology Center, Boston, MA, USA
Akio Suzumura, M.D., Ph.D. Department of Neuroimmunology, Research
Institute of Environmental Medicine, Nagoya University, Nagoya, Japan
Marie-Ève Tremblay, Ph.D. Axe Neurosciences, Centre de recherche du CHU de
Québec, and Department of Molecular Medicine, Université Laval, Québec, QC,
Canada
Hiroaki Wake, M.D., Ph.D. National Institute for Physiological Sciences,
Okazaki, Japan
Xiaohui Wang, Ph.D. Chemical Biology Laboratory, Changchun Institute of
Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin, China
Department of Psychology and the Center for Neuroscience, Department of
Chemistry and Biochemistry and BioFrontiers Institute, University of Colorado at
Boulder, Boulder, CO, USA
Linda R. Watkins, Ph.D. Department of Psychology and the Center for
Neuroscience, University of Colorado at Boulder, Boulder, CO, USA
Jyoti J. Watters, Ph.D. Department of Comparative Biosciences, University of
Wisconsin, Madison, Madison, WI, USA
Hang Yin, Ph.D. Department of Chemistry and Biochemistry and BioFrontiers
Institute, University of Colorado at Boulder, Boulder, CO, USA
 Part I
The General Setting
Chapter 1
Introduction

Amanda Sierra and Marie-Ève Tremblay

Abstract Microglia are taking a central role in the Neuroscience arena nowadays,
following a series of recent discoveries challenging their traditional portrayal as
simple “brain macrophages”. Indeed, microglia have unique properties compared
with other cells of the immune system, including their origin from the embryonic
yolk sac, their capacity for self-renewal, and the extreme motility of their processes
which closely interact with all the neighboring elements of the nervous parenchyma.
In parallel, we have just begun to unravel novel roles for microglia during normal
physiological conditions that are impacting our understanding of their crucial par-
ticipation in pathological situations. Throughout the chapters of this book, some of
the most intriguing open questions in microglial research today are transversally
discussed. How is microglial population homeostasis maintained? Are there hetero-
geneous subpopulations of microglia? Can microglia respond to neuronal activity,
and alter it? Do microglia interact with other types of immune cells? Are microglia
beneficial or detrimental in diseases of the central nervous system? Are there novel
tools to specifically manipulate microglia in a non-invasive manner? We do not have
the answers yet for most of these questions, but in the next few years their investiga-
tion will will undoubtly continue to shape the future of Neuroscience in unexpected
manners.

A. Sierra, Ph.D. (*)

Achucarro Basque Center for Neuroscience, University of the Basque Country EHU/UPV,
Ikerbasque Foundation, Bizkaia Science and Technology Park, Building 205, Zamudio,
Bizkaia 48116, Spain
e-mail: [email protected]
M.-È. Tremblay, Ph.D. (*)
Axe Neurosciences, Centre de Recherche du CHU de Québec, and Department
of Molecular Medicine, Université Laval, Québec, QC, Canada
e-mail: [email protected]

© Springer Science+Business Media New York 2014 3

M.-È. Tremblay, A. Sierra (eds.), Microglia in Health and Disease,
DOI 10.1007/978-1-4939-1429-6_1
4 A. Sierra and M.-È. Tremblay

Keywords Microglia • Origin • Motility • Homeostasis • Heterogeneity • Neuronal

activity • Central nervous system • Diseases • Experimental tools

Microglia have been traditionally perceived simply as brain macrophages controlling

a mostly detrimental inflammatory response and have been for ages confined to the
darkest and most pejorative corner of morphological, observational descriptions.
With the recent development of non-invasive tools to visualize microglial dynamics
and manipulate their gene expression, without inducing their pathological transfor-
mation in response to experimental procedures, microglia have taken the center
stage in neuroscience. High impact papers have just started pouring in, discovering
new roles for microglial cells in various contexts of health and disease. At the core
of this turmoil has been the realization that microglia are not, indeed, like other
macrophages.
Microglia do share many characteristics with circulating monocytes and macro-
phages residing in other tissues, including the expression of surface markers, recep-
tors for pathogen and danger-associated molecules, intracellular signalling pathways
involved with innate immunity, and above all, the capacity to phagocytose cellular
debris and release various types of pro-inflammatory mediators. In fact, this similar-
ity has hindered the understanding of microglia, and for a long time, macrophage
behaviors were simply extrapolated to microglia. However, microglia have a
distinctive origin, coming from primitive precursors in the yolk sac that invade the
developing brain during early embryonic stages, whereas most hematopoietic lin-
eages are generated later in the embryonic fetal liver. Furthermore, monocytes and
macrophages are continuously replaced throughout adulthood, from bone
marrow-derived precursors, whereas microglia are a long-lived population that self-
renews in the healthy central nervous system (CNS) parenchyma, at least when the
blood–brain barrier remains intact. Microglia also display unique properties that
render them exquisitely adapted to their CNS environment, most notably the
extreme dynamism of their processes, which interact intimately with all the other
parenchymal elements, including neuronal bodies, processes, and synapses, astro-
cytes, neural progenitors, oligodendrocytes, and blood vessels, during normal phys-
iological conditions.
The recent discoveries have opened many functional possibilities for microglia,
beyond merely passive immune surveillance, but have also raised many more
questions about their homeostasis and heterogeneity, regulation by neuronal activity,
interactions with the other types of CNS and immune cells, and their active versus
passive contributions to diseases, as well as serious concerns regarding the specificity
of the tools commonly used for studying microglia.
Microglial homeostasis. Upon invasion of the CNS during embryonic develop-
ment, microglial cells are well known to differentiate, migrate, and occupy nonover-
lapping territories, but the molecular signals recruited to establish and maintain
their territorial organisation are still undetermined. Little is known also regarding