MINDING GLIAL CELLS IN THE NOVEL UNDERSTANDINGS OF MENTAL ILLNESS EDITED BY : Takahiro A. Kato, Aye M. Myint and Johann Steiner PUBLISHED IN : Frontiers in Cellular Neuroscience 1 April 2017 | G lial Cells and Mental Illness Frontiers in Cellular Neuroscience Frontiers Copyright Statement © Copyright 2007-2017 Frontiers Media SA. All rights reserved. All content included on this site, such as text, graphics, logos, button icons, images, video/audio clips, downloads, data compilations and software, is the property of or is licensed to Frontiers Media SA (“Frontiers”) or its licensees and/or subcontractors. The copyright in the text of individual articles is the property of their respective authors, subject to a license granted to Frontiers. The compilation of articles constituting this e-book, wherever published, as well as the compilation of all other content on this site, is the exclusive property of Frontiers. 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For the full conditions see the Conditions for Authors and the Conditions for Website Use. ISSN 1664-8714 ISBN 978-2-88945-157-9 DOI 10.3389/978-2-88945-157-9 About Frontiers Frontiers is more than just an open-access publisher of scholarly articles: it is a pioneering approach to the world of academia, radically improving the way scholarly research is managed. The grand vision of Frontiers is a world where all people have an equal opportunity to seek, share and generate knowledge. Frontiers provides immediate and permanent online open access to all its publications, but this alone is not enough to realize our grand goals. Frontiers Journal Series The Frontiers Journal Series is a multi-tier and interdisciplinary set of open-access, online journals, promising a paradigm shift from the current review, selection and dissemination processes in academic publishing. 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Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: researchtopics@frontiersin.org 2 April 2017 | G lial Cells and Mental Illness Frontiers in Cellular Neuroscience MINDING GLIAL CELLS IN THE NOVEL UNDERSTANDINGS OF MENTAL ILLNESS HLA-DR immunopositive microglial cell (dorsolateral prefrontal cortex of a schizophrenia patient from the Magdeburg Brain Bank; Johann Steiner, Henrik Dobrowolny and Konstantin Schlaaff) Topic Editors: Takahiro A. Kato, Kyushu University, Japan Aye M. Myint, Ludwig-Maximilians-University, Germany Johann Steiner, Otto-von-Guericke University Magdeburg, Germany Traditionally, abnormalities of neurons and neuronal networks including synaptic abnormalities and disturbance of neurotransmitters have dominantly been believed to be the main causes of psychiatric disorders. Recent cellular neuroscience has revealed various unknown roles of glial cells such as astrocytes, oligodendrocytes and microglia. These glial cells have proved to contin- uously contact with neurons /synapses, and have been shown to play important roles in brain development, homeostasis and various brain functions. Beyond the classic neuronal doctrine, accumulating evidence has suggested that abnormalities and disturbances of neuron-glia cross- talk may induce psychiatric disorders, while these mechanisms have not been well understood. 3 April 2017 | G lial Cells and Mental Illness Frontiers in Cellular Neuroscience This Research Topic of the Frontiers in Cellular Neuroscience provides an overview on the most recent developments and ideas in the study of glial cells (astrocytes, oligodendrocytes and micro- glia) focusing on psychiatric disorders such as schizophrenia, mood disorders and autism. Not only molecular, cellular and pharmacological approaches using in vitro / in vivo experimental methods but also translational research approaches are presented. Novel translational research approaches, for example, using novel techniques such as induced pluripotent stem (iPS) cells, may lead to novel solutions. We believe that investigations to clarify the correlation between glial cells and psychiatric dis- orders contribute to a novel understanding of the pathophysiology of these disorders and the development of effective treatment strategies. Citation: Kato, T. A., Myint, A. M., Steiner, J., eds. (2017). Minding Glial Cells in the Novel Understandings of Mental Illness. Lausanne: Frontiers Media. doi: 10.3389/978-2-88945-157-9 4 April 2017 | G lial Cells and Mental Illness Frontiers in Cellular Neuroscience Table of Contents 07 Editorial: Minding Glial Cells in the Novel Understandings of Mental Illness Takahiro A. Kato, Aye M. Myint and Johann Steiner 10 A New Outlook on Mental Illnesses: Glial Involvement Beyond the Glue Maha Elsayed and Pierre J. Magistretti Human postmortem research: 30 Reduced density of glutamine synthetase immunoreactive astrocytes in different cortical areas in major depression but not in bipolar I disorder Hans-Gert Bernstein, Gabriela Meyer-Lotz, Henrik Dobrowolny, Jana Bannier, Johann Steiner, Martin Walter and Bernhard Bogerts 42 Oligodendrocyte and Interneuron Density in Hippocampal Subfields in Schizophrenia and Association of Oligodendrocyte Number with Cognitive Deficits Peter Falkai, Johann Steiner, Berend Malchow, Jawid Shariati, Andreas Knaus, Hans-Gert Bernstein, Thomas Schneider-Axmann, Theo Kraus, Alkomiet Hasan, Bernhard Bogerts and Andrea Schmitt Glial protein blood markers: 55 Serum S100B Protein is Specifically Related to White Matter Changes in Schizophrenia Berko Milleit, Stefan Smesny, Matthias Rothermundt, Christoph Preul, Matthias L. Schroeter, Christof von Eiff, Gerald Ponath, Christine Milleit, Heinrich Sauer and Christian Gaser 69 Serum S100B Is Related to Illness Duration and Clinical Symptoms in Schizophrenia—A Meta-Regression Analysis Katharina Schümberg, Maryna Polyakova, Johann Steiner and Matthias L. Schroeter Blood cells as tools to model microglia-like cells: 80 Linking Activation of Microglia and Peripheral Monocytic Cells to the Pathophysiology of Psychiatric Disorders Yuta Takahashi, Zhiqian Yu, Mai Sakai and Hiroaki Tomita 89 Introducing directly induced microglia-like (iMG) cells from fresh human monocytes: a novel translational research tool for psychiatric disorders Masahiro Ohgidani, Takahiro A. Kato and Shigenobu Kanba 5 April 2017 | G lial Cells and Mental Illness Frontiers in Cellular Neuroscience Animal models: a) Maternal immune activation: 94 Changes in Astroglial Markers in a Maternal Immune Activation Model of Schizophrenia in Wistar Rats are Dependent on Sex Daniela F . de Souza, Krista M. Wartchow, Paula S. Lunardi, Giovana Brolese, Lucas S. Tortorelli, Cristiane Batassini, Regina Biasibetti and Carlos-Alberto Gonçalves 105 Maternal immune activation evoked by polyinosinic:polycytidylic acid does not evoke microglial cell activation in the embryo Silke Smolders, Sophie M. T. Smolders, Nina Swinnen, Annette Gärtner, Jean-Michel Rigo, Pascal Legendre and Bert Brône 119 Commentary: Maternal immune activation evoked by polyinosinic: polycytidylic acid does not evoke microglial cell activation in the embryo Hans-Gert Bernstein, Yael Piontkewitz and Gerburg Keilhoff b) Cuprizone-induced demyelination and experimental autoimmune encephalomyelitis: 122 Quetiapine Inhibits Microglial Activation by Neutralizing Abnormal STIM1- Mediated Intercellular Calcium Homeostasis and Promotes Myelin Repair in a Cuprizone-Induced Mouse Model of Demyelination Hanzhi Wang, Shubao Liu, Yanping Tian, Xiyan Wu, Yangtao He, Chengren Li, Michael Namaka, Jiming Kong, Hongli Li and Lan Xiao 133 Exploring the role of microglia in mood disorders associated with experimental multiple sclerosis Antonietta Gentile, Francesca De Vito, Diego Fresegna, Alessandra Musella, Fabio Buttari, Silvia Bullitta, Georgia Mandolesi and Diego Centonze c) NMDA glutamate receptor modulation and impaired oligodendrocyte maturation: 143 Long-term NMDAR antagonism correlates reduced astrocytic glutamate uptake with anxiety-like phenotype Eduardo R. Zimmer, Vitor R. Torrez, Eduardo Kalinine, Marina C. Augustin, Kamila C. Zenki, Roberto F . Almeida, Gisele Hansel, Alexandre P . Muller, Diogo O. Souza, Rodrigo Machado-Vieira and Luis V. Portela [correction of Zimmer-paper] 151 Impairment of Oligodendroglia Maturation Leads to Aberrantly Increased Cortical Glutamate and Anxiety-Like Behaviors in Juvenile Mice Xianjun Chen, Weiguo Zhang, Tao Li, Yu Guo, Yanping Tian, Fei Wang, Shubao Liu, Hai-Ying Shen, Yue Feng and Lan Xiao Proteome, metabolome and cellular analyses: 162 Proteomics Research in Schizophrenia Katarina Davalieva, Ivana Maleva Kostovska and Andrew J. Dwork 184 MK-801 treatment affects glycolysis in oligodendrocytes more than in astrocytes and neuronal cells: insights for schizophrenia Paul C. Guest, Keiko Iwata, Takahiro A. Kato, Johann Steiner, Andrea Schmitt, Christoph W. Turck and Daniel Martins-de-Souza 6 April 2017 | G lial Cells and Mental Illness Frontiers in Cellular Neuroscience 194 Effect of MK-801 and Clozapine on the Proteome of Cultured Human Oligodendrocytes Juliana S. Cassoli, Keiko Iwata, Johann Steiner, Paul C. Guest, Christoph W. Turck, Juliana M. Nascimento and Daniel Martins-de-Souza, 208 Clozapine promotes glycolysis and myelin lipid synthesis in cultured oligodendrocytes Johann Steiner, Daniel Martins-de-Souza, Kolja Schiltz, Zoltan Sarnyai, Sabine Westphal, Berend Isermann, Henrik Dobrowolny, Christoph W. Turck, Bernhard Bogerts, Hans-Gert Bernstein, Tamas L. Horvath, Lorenz Schild and Gerburg Keilhoff 219 Microglial intracellular Ca 2+ signaling as a target of antipsychotic actions for the treatment of schizophrenia Yoshito Mizoguchi, Takahiro A. Kato, Hideki Horikawa and Akira Monji 224 Advancements in the Underlying Pathogenesis of Schizophrenia: Implications of DNA Methylation in Glial Cells Xing-Shu Chen, Nanxin Huang, Namaka Michael and Lan Xiao Theories and hypotheses linking psychiatric disorders with glial dysfunction: 232 Potential primary roles of glial cells in the mechanisms of psychiatric disorders Kazuhiko Yamamuro, Sohei Kimoto, Kenneth M. Rosen, Toshifumi Kishimoto and Manabu Makinodan 243 Astrocytes and Microglia and Their Potential Link with Autism Spectrum Disorders Francesco Petrelli, Luca Pucci and Paola Bezzi 251 Functional alterations of astrocytes in mental disorders: pharmacological significance as a drug target Yutaka Koyama 263 Possible role of glial cells in the relationship between thyroid dysfunction and mental disorders Mami Noda 270 Understanding the role of P2X7 in affective disorders—are glial cells the major players? Leanne Stokes, Sarah J. Spencer and Trisha A. Jenkins EDITORIAL published: 28 February 2017 doi: 10.3389/fncel.2017.00048 Frontiers in Cellular Neuroscience | www.frontiersin.org February 2017 | Volume 11 | Article 48 | Edited by: Egidio D‘Angelo, University of Pavia, Italy *Correspondence: Takahiro A. Kato takahiro@npsych.med.kyushu-u.ac.jp Received: 13 January 2017 Accepted: 13 February 2017 Published: 28 February 2017 Citation: Kato TA, Myint AM and Steiner J (2017) Editorial: Minding Glial Cells in the Novel Understandings of Mental Illness. Front. Cell. Neurosci. 11:48. doi: 10.3389/fncel.2017.00048 Editorial: Minding Glial Cells in the Novel Understandings of Mental Illness Takahiro A. Kato 1, 2 *, Aye M. Myint 3 and Johann Steiner 4 1 Department of Neuropsychiatry, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan, 2 Brain Research Unit, Innovation Center for Medical Redox Navigation, Kyushu University, Fukuoka, Japan, 3 Department of Psychiatry, Ludwig-Maximilians-University, Munich, Germany, 4 Department of Psychiatry, Otto-von-Guericke University Magdeburg, Magdeburg, Germany Keywords: microglia, psychiatric disorders, depression, schizophrenia, autism, astrocytes, oligodendrocytes, autism spectrum disorders Editorial on the Research Topic Minding Glial Cells in the Novel Understandings of Mental Illness During the last few decades, it has been assumed that dysfunctions of neurons and neuronal networks including synaptic abnormalities and consecutive disturbances of neurotransmitters are the main and sole causes of psychiatric disorders. Recent neuroscience has revealed various previously unknown roles of glial cells such as astrocytes, oligodendrocytes, and microglia as modulators of neurotransmission. These glial cells have proved to continuously contact with neurons/synapses, and have been shown to play important roles in brain development, homeostasis, and various brain functions. Beyond the classic neuronal doctrine of neuropsychiatry, accumulating evidence has suggested that abnormalities and disturbances of the crosstalk between neurons and glial cells may induce mental dysfunction and be a risk factor for the manifestation of psychiatric disorders. However, these mechanisms have yet to be well-understood. This research topic of “the Frontiers in Cellular Neuroscience” has focused on the most recent developments and ideas in the study of glial cells (astrocytes, oligodendrocytes, and microglia) targeting psychiatric disorders such as schizophrenia, mood disorders, and autism. Here, we publish more than 20 articles including original research, review, perspective, and commentary. While all of the articles are focused on psychiatric disorders, a variety of methods/approaches have been employed from molecular, cellular, and pharmacological approaches using in vitro / in vivo experimental methods to translational approaches using human tissues. Human postmortem research using brain tissues of patients with psychiatric disorders is one of the most important research approaches in biological psychiatry. In this research topic, Bernstein et al. reported a reduced density of glutamine synthetase immunoreactive astrocytes in different cortical areas in major depression but not in bipolar I disorder. Falkai et al. revealed an interaction between a decrease of oligodendrocyte and interneuron density in the hippocampus of schizophrenia patients and discussed the association of oligodendrocyte number with cognitive deficits, proposing that a decreased number of oligodendrocytes in the anterior, and entire hippocampus may be involved in cognitive deficits by impairing the connectivity of this structure in schizophrenia. On the other hand, various novel approaches of brain imaging techniques have been developed to reveal glial dysfunctions in living patients with psychiatric disorders (Kato et al., 2013a). Peripheral blood markers are also suggested to be useful biomarkers of psychiatric disorders. For example, S100B has been considered as a glial marker protein, particular to oligodendrocytes and astrocytes. It passes the blood brain barrier and is detectable in peripheral blood. In this 7 Kato et al. Glial Cells and Mental Illness research topic, Schumberg et al. reported that serum S100B is related to illness duration and clinical symptoms in schizophrenia by a meta-regression analysis. Furthermore, combination analysis between brain imaging data and blood data is becoming one of the most highlighted approaches in psychiatry. Milleit et al. conducted an association analysis between brain imaging data of voxel based morphometry (VBM) and serum S100B concentrations in unmedicated patients with schizophrenia and healthy volunteers, and revealed that serum S100B protein is specifically related to white matter changes in patients with schizophrenia. This report suggests the involvement of S100B in an ongoing and dynamic process associated with structural brain changes and brain connectivity in schizophrenia. As mentioned above, peripheral blood markers including components/materials of serum, plasma, and genes are possible useful biomarkers of psychiatric disorders. In addition, blood cells themselves have also been highlighted as possible biomarkers. Microglia and peripheral monocytes (monocytic cells) are both of mesodermal origin. Takahashi et al. discussed this linkage focusing on the activation of microglia and peripheral monocytes to understand the pathophysiology of psychiatric disorders. Ohgidani et al. introduced a novel translational tool for neuropsychiatric disorders, called “induced microglia-like (iMG) cells,” which can be produced within 2 weeks from fresh human monocytes by adding only two cytokines (GM-CSF and IL-34). They have recently reported on the suitability of the iMG cells to study and understand microglial pathophysiology in patients with schizophrenia and bipolar disorder (Sato-Kasai et al., 2016; Ohgidani et al., 2017). Alternatively, human induced pluripotent stem (iPS) cells- and embryonic stem (ES)-oriented microglia-like cells (termed pMGLs) may also prove to be suitable tools (Muffat et al., 2016). We believe that both the generation of iMG cells and pMGLs will provide a strong method to reveal the potential contribution of microglial cells in psychiatric disorders in more detail. In spite of great advances in human research tools as shown above, animal models are still thought to be essential for psychiatric research. Epidemiological studies suggest that prenatal exposure to bacterial and viral infection is an important environmental risk factor for schizophrenia. The maternal immune activation (MIA) animal model is used to study how an insult directed at the maternal host can have adverse effects on the fetus, leading to behavioral and neurochemical changes later in life. In this research topic, de Souza et al. observed an upregulation of astroglial markers (S100B and GFAP) in a MIA model of schizophrenia by LPS in Wistar rats; the brain-regional expression pattern was sex-dependent. Smolders et al. reported that MIA evoked by polyinosinic:polycytidylic acid (polyI:C) does not evoke microglial cell activation in the embryo. This report suggests that the behavioral and neurological alterations in offspring cannot be related to the alteration of the activation state of embryonic microglial cells. Their in vitro studies also indicated that microglia cannot be directly activated by poly (I:C) or IL- 6 exposure. However, recent studies in other research groups indicate that there is an increase in microglial density in different brain regions in the adult poly (I:C) MIA offspring (postnatal and adult age) (Juckel et al., 2011; Manitz et al., 2013). As commentary responding to Smolders et al., Bernstein et al. suggested the role of astrocytic activation in the brains of MIA offspring. Further investigations are needed to understand the relevance of microglial and astrocytic activation in each developmental stage of the MIA models. On the other hand, the Cuprizone-treatment rodent model, one of the classical models of multiple sclerosis (MS), is now regarded as a useful model of schizophrenia (Xiao et al., 2008), showing a series of dysfunctions of glial cells such as microglia, astrocytes, and oligodendrocytes. Wang et al. reported that quetiapine inhibits microglial activation by neutralizing abnormal STIM1-mediated intercellular calcium homeostasis and promoting myelin repair in a cuprizone-induced mouse model of demyelination. Interestingly, Gentile et al. proposed the merit of utilizing the behavioral and neuro-glial studies with experimental autoimmune encephalomyelitis (EAE)—the most famous animal model of MS in order to explore the role of microglia in mood disorders. This special issue also contains two mice model studies focusing on anxiety and glial cells. Zimmer et al. demonstrated that long-term administration of memantine (a NMDAR antagonist) induced anxiety-like behaviors, and decreased glutamate uptake activity in both the frontoparietal cortex and hippocampus without altering the immunocontents of the astroglial glutamate transporters GLT-1 and GLAST. Chen et al. reported that impairment of oligodendroglia maturation leads to aberrantly increased cortical glutamate and anxiety-like behaviors in juvenile mice. High throughput technology of genome analysis, especially genome-wide association study (GWAS), has shown various candidate genes of psychiatric disorders such as schizophrenia and bipolar disorder (Psychiatric GWAS Consortium Bipolar Disorder Working Group, 2011; Ripke et al., 2013; Schizophrenia Working Group of the Psychiatric Genomics, 2014). Apart from genome analyses, proteome and metabolome analyses are expected to reveal unknown biological aspects of psychiatric disorders (Kaddurah-Daouk and Krishnan, 2009; Domenici et al., 2010; Setoyama et al., 2016). In this research topic, Davalieva et al. reviewed the recent advances of proteomic research in schizophrenia. Three original research articles applying the proteomic analysis of glial cells with a pharmacological intervention are also included in this topic. Guest et al. reported that MK-801 treatment affects glycolysis in oligodendrocytes more than in astrocytes and neuronal cells. Cassoli et al. compared effects of MK-801 and the antipsychotic drug clozapine on the proteome of cultured oligodendrocytes. In addition, focusing in a hypothesis-driven study on energy metabolism, Steiner et al. compared the typical antipsychotic drug haloperidol with the atypical antipsychotic compound clozapine; only the latter promoted glycolysis and myelin lipid synthesis in cultured oligodendrocytes. These data suggest that psychotropic drugs, originally developed for the modulation of neurons and/or synaptic neurotransmission, are also acting on astrocytes and oligodendrocytes. Similarly, recent in vitro studies using rodent microglial cells have revealed that psychotropic drugs, especially antipsychotics and antidepressants may also Frontiers in Cellular Neuroscience | www.frontiersin.org February 2017 | Volume 11 | Article 48 | 8 Kato et al. Glial Cells and Mental Illness directly modulate microglial cells (Kato et al., 2011, 2013b), however the underlying signal transduction mechanisms have not been well clarified. In this research topic, Mizoguchi et al. proposed that microglial intracellular Ca 2 + signaling may be an important target of antipsychotic actions. On the other hand, epigenetic mechanisms may be important disease modifiers. In line with this idea, Chen et al. introduced the recent topic of DNA methylation in glial cells for further research of schizophrenia. In this research topic, we have included several review papers proposing interesting theories and hypotheses linking psychiatric disorders with dysfunctions of glial cells: Yamamuro et al. introduced potential primary roles of glial cells in the underlying mechanisms of psychiatric disorders. Petrelli et al. discussed the possible link between autism spectrum disorders and glial cells especially astrocytes and microglia. Koyama introduced functional alterations of astrocytes in mental disorders, and proposed pharmacological modulation of astrocytes as a novel drug target. Noda depicted a possible role of glial cells in the relationship between thyroid dysfunction and mental disorders. And finally, Stokes et al. discussed the recent evidence for an involvement of microglial and/or astrocytic P2X7 in the pathophysiology of depressive disorders. We are very pleased to publish a broad spectrum of papers focusing on glial cells in the field of psychiatry utilizing multi- dimensional approaches. We believe that further investigations to clarify the correlation between glial cells and psychiatric disorders will contribute to a novel understanding of the pathophysiology of mental illnesses and the development of effective treatment strategies. AUTHOR CONTRIBUTIONS All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication. REFERENCES Domenici, E., Wille, D. R., Tozzi, F., Prokopenko, I., Miller, S., Mckeown, A., et al. (2010). 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Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427. doi: 10.1038/nature13595 Setoyama, D., Kato, T. A., Hashimoto, R., Kunugi, H., Hattori, K., Hayakawa, K., et al. (2016). Plasma metabolites predict severity of depression and suicidal ideation in psychiatric patients-a multicenter pilot analysis. PLoS ONE 11:e0165267. doi: 10.1371/journal.pone. 0165267 Xiao, L., Xu, H., Zhang, Y., Wei, Z., He, J., Jiang, W., et al. (2008). Quetiapine facilitates oligodendrocyte development and prevents mice from myelin breakdown and behavioral changes. Mol. Psychiatry 13, 697–708. doi: 10.1038/sj.mp.4002064 Conflict of Interest Statement: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Copyright © 2017 Kato, Myint and Steiner. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Frontiers in Cellular Neuroscience | www.frontiersin.org February 2017 | Volume 11 | Article 48 | 9 REVIEW published: 16 December 2015 doi: 10.3389/fncel.2015.00468 A New Outlook on Mental Illnesses: Glial Involvement Beyond the Glue Maha Elsayed 1 and Pierre J. Magistretti 1,2,3 * 1 Laboratory of Neuroenergetics and Cellular Dynamics, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland, 2 Division of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia, 3 Department of Psychiatry, Center for Psychiatric Neurosciences, University of Lausanne, Lausanne, Switzerland Edited by: Johann Steiner, University of Magdeburg, Germany Reviewed by: Björn Spittau, Albert-Ludwigs-University Freiburg, Germany Cai Song, Guangdong Ocean University and China Medical University, China *Correspondence: Pierre J. Magistretti pierre.magistretti@kaust.edu.sa Received: 21 July 2015 Accepted: 16 November 2015 Published: 16 December 2015 Citation: Elsayed M and Magistretti PJ (2015) A New Outlook on Mental Illnesses: Glial Involvement Beyond the Glue. Front. Cell. Neurosci. 9:468. doi: 10.3389/fncel.2015.00468 Mental illnesses have long been perceived as the exclusive consequence of abnormalities in neuronal functioning. Until recently, the role of glial cells in the pathophysiology of mental diseases has largely been overlooked. However recently, multiple lines of evidence suggest more diverse and significant functions of glia with behavior-altering effects. The newly ascribed roles of astrocytes, oligodendrocytes and microglia have led to their examination in brain pathology and mental illnesses. Indeed, abnormalities in glial function, structure and density have been observed in postmortem brain studies of subjects diagnosed with mental illnesses. In this review, we discuss the newly identified functions of glia and highlight the findings of glial abnormalities in psychiatric disorders. We discuss these preclinical and clinical findings implicating the involvement of glial cells in mental illnesses with the perspective that these cells may represent a new target for treatment. Keywords: psychiatric disorder, glia, astrocyte, oligodendrocyte, microglia, NG2 glia, mood, cognition INTRODUCTION Treatment of mental illnesses dates back to ancient times where imprisonment and confinement to chains were the mode of action to control what was perceived as influences of witchcraft and supernatural forces. With the introduction of Hippocratic medicine back in the 4th century B.C., mental illness had a physical attribute and the cause was linked to humoral imbalances. Though, the idea of demons and supernatural forces still persisted. Towards the end of the 18th century, the idea of mental illness as a disease of the mind rather than the body began to develop and it was towards the mid-19th century when it became viewed as a disease of the brain. Though, the term mental was coined to it till this day, mainly due to the lack of cerebral pathology at macroscopic and microscopic levels at the time (Kendell, 2001). In the 1950s, psychopharmacology emerged. Following serendipitous clinical observations, chlorpromazine (dopamine antagonist) and iproniazid (monoamine oxidase inhibitor) were observed to have antipsychotic and antidepressant effects respectively (Deverteuil and Lehmann, 1958; Ban, 2007; Nestler and Hyman, 2010). These observations paved the way to the development of current psychotropic drugs whose pharmacology is essentially based on monoamine neurotransmission. Despite the availability of these psychoactive medicines, there remains however an increasing prevalence, undeniable disability, economic and social burden (Hyman, 2008). The reason for the lack of success is that these psychotherapeutic drugs were not founded on real evidence of underlying pathology. Instead, the reverse engineering of these drugs lead to the identification of molecular targets that are possibly not the actual culprit. Frontiers in Cellular Neuroscience | www.frontiersin.org December 2015 | Volume 9 | Article 468 | 10 Elsayed and Magistretti Glial Involvement Beyond the Glue With the emergence of in vivo brain imaging techniques and improvement in the methods of microscopy, immunocytochemistry and stereology, interest in re-examining cerebral pathology at the macro- and micro-scopic level ensued (Rajkowska et al., 1999). The microscopic approach has notably brought glial cells to light with newly identified functions. With access to the right tools, findings of glia pathology in psychiatric disorders began to surface (Di Benedetto and Rupprecht, 2013). In this review, we will introduce the different types and functions of glia and then discuss findings implicating their involvement in the different types of mental illnesses. GLIA IN BRAIN FUNCTION AND HEALTH While the legacy of the last century of research in psychiatry has centered on deciphering the role of neuronal systems in brain functions in health and disease, little attention has been paid to non-neuronal cells. Glial cells in fact outnumber neurons in several areas of the human brain (Kandel, 2000; Pelvig et al., 2008; Azevedo et al., 2009; Herculano-Houzel, 2011). Interestingly enough, this ratio is decreased in rodents (Nedergaard et al., 2003; Rajkowska and Miguel-Hidalgo, 2007; Herculano-Houzel, 2011) indicating that increased glial densities is associated with higher brain functions. The term neuroglia was initially coined by the German anatomist Rudolf Virchow in 1856 to refer to a scaffolding material. Traditionally seen as silent supportive cells, growing evidence suggest a more dynamic and active function. Glial cells provide a source of metabolic energy and growth/neurotrophic factors, are involved in regulating synaptic plasticity, modulating neuronal excitability, neurotransmitter modulation/reuptake and relay of information, among other functions. In short, they have emerged to be important players that alter neuronal state and connectivity. Based on lineages, there are two types of Central Nervous System (CNS) glia: macroglia and microglia. Macroglia (astrocyte, oligodendrocyte) arise from ectoderm while microglia originate from monocyte-macrophage lineage (Ventura and Goldman, 2006; Rajkowska and Miguel-Hidalgo, 2007). Each type has a specialized function and a unique morphology (Ventura and Goldman, 2006; Rajkowska and Miguel-Hidalgo, 2007). While oligodendrocytes and microglia were long thought to have specialized functions, astrocytes proved to be the most complex and functionally diverse. Astrocytes The term astrocyte was initially described by Von Lenhossek in 1893 based on its star-like morphology. It turns out that astrocytes are quite heterogeneous in cell morphology, a fact that also reflects inherent functional specialization. Astrocytes can be categorized into at least five different types: (1) white matter astrocytes which take on a star shape; (2) gray matter astrocytes, which have a less complex shape; (3) ependymal astrocytes, which are stained positive for a marker of astrocytes, GFAP, and are found in the stem cell niches of the brain; (4) radial glia found within ventricular zone which originally provide a scaffold for migrating neurons during brain development; and (5) perivascular, also GFAP+, whose end-feet are in close proximity to blood vessels (Claycomb et al., 2013). Novel discoveries on the diverse functions of astrocytes have challenged the long-time held dogma that astrocytes are merely passive cells. From an evolutionary point of view, the ratio of astrocytes to neurons and the morphology of astrocytes increase with the complexity of brain functions (Oberheim et al., 2009; Pereira and Furlan, 2010; Herculano-Houzel, 2011). The diversity of astrocytic roles are discussed below and range from local modulation of information processing within a synapse to brain large-scale integrative functions, and extend to interactions with the vasculature system and the immune system. Some of these functions support its involvement in cognitive and mood functions and the ones pertinent to psychiatric illnesses are discussed below. Neurovascular Unit Astrocytes form a bridging gap, coupling the vasculature system with neuronal circuits. The surface of intraparenchymal capillaries is covered at 99% by astrocytic end-feet (Kacem et al., 1998). Astrocytic end feet wrap around the endothelium of blood vessels and via this contact, they can influence cerebral blood flow (Takano et al., 2006; Magistretti and Allaman, 2015) and control the transport of substances in and out of the brain to ensure proper brain homeostasis (Abbott et al., 2006). Metabolic Coupling Astrocytes have been shown to support neurons metabolically. Astrocytes express glucose transporters of the GLUT1 type along their astrocytic end feet (Allaman and Magistretti, 2013). Upon increased neuronal activity and glutamate reuptake by astrocyte- specific glutamate transporters, a sequence of events is triggered resulting in the uptake of glucose from blood vessels and erobic glycolysis, a process also known as the Astrocyte Neuron Lactate Shuttle (for review, see Magistretti and Allaman, 2015). With Lactate being the end product, it is released into the interstitial space for neuronal uptake (Walz and Mukerji, 1988; Pellerin and Magistretti, 1994; Chuquet et al., 2010). Furthermore, astrocytes are the on