DOCSLIB.ORG

Subsets Underlies IL-6 Signaling in Glial Β Differential

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Subsets Underlies IL-6 Signaling in Glial Β Differential Differential TGF-β Signaling in Glial Subsets Underlies IL-6−Mediated Epileptogenesis in Mice This information is current as Nitzan Levy, Dan Z. Milikovsky, Gytis Baranauskas, of October 1, 2021. Ekaterina Vinogradov, Yaron David, Maya Ketzef, Shai Abutbul, Itai Weissberg, Lyn Kamintsky, Ilya Fleidervish, Alon Friedman and Alon Monsonego J Immunol 2015; 195:1713-1722; Prepublished online 1 July 2015; doi: 10.4049/jimmunol.1401446 Downloaded from http://www.jimmunol.org/content/195/4/1713 References This article cites 50 articles, 13 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/195/4/1713.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on October 1, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Differential TGF-b Signaling in Glial Subsets Underlies IL-6–Mediated Epileptogenesis in Mice Nitzan Levy,*,†,1 Dan Z. Milikovsky,†,1 Gytis Baranauskas,† Ekaterina Vinogradov,* Yaron David,† Maya Ketzef,† Shai Abutbul,* Itai Weissberg,† Lyn Kamintsky,† Ilya Fleidervish,† Alon Friedman,†,‡,2 and Alon Monsonego*,2 TGF-b1 is a master cytokine in immune regulation, orchestrating both pro- and anti-inflammatory reactions. Recent studies show that whereas TGF-b1 induces a quiescent microglia phenotype, it plays a pathogenic role in the neurovascular unit and triggers neuronal hyperexcitability and epileptogenesis. In this study, we show that, in primary glial cultures, TGF-b signaling induces rapid upregulation of the cytokine IL-6 in astrocytes, but not in microglia, via enhanced expression, phosphorylation, and nuclear translocation of SMAD2/3. Electrophysiological recordings show that administration of IL-6 increases cortical excitability, cul- minating in epileptiform discharges in vitro and spontaneous seizures in C57BL/6 mice. Intracellular recordings from layer V Downloaded from pyramidal cells in neocortical slices obtained from IL-6–treated mice show that during epileptogenesis, the cells respond to repetitive orthodromic activation with prolonged after-depolarization with no apparent changes in intrinsic membrane properties. Notably, TGF-b1–induced IL-6 upregulation occurs in brains of FVB/N but not in brains of C57BL/6 mice. Overall, our data suggest that TGF-b signaling in the brain can cause astrocyte activation whereby IL-6 upregulation results in dysregulation of astrocyte–neuronal interactions and neuronal hyperexcitability. Whereas IL-6 is epileptogenic in C57BL/6 mice, its upregulation by TGF-b1 is more profound in FVB/N mice characterized as a relatively more susceptible strain to seizure-induced cell death. http://www.jimmunol.org/ The Journal of Immunology, 2015, 195: 1713–1722. pilepsy is one of the most common neurologic disorders signaling cascade (through SMAD2/3 phosphorylation), and in- and is estimated to affect up to 1% of the population duces an astrocytic transcriptional response with proinflammatory E worldwide (1). Postinjury epilepsy often develops fol- characteristics (10, 14–16). Furthermore, losartan, previously lowing brain insults, including ischemic or traumatic injury, as identified as a blocker of peripheral TGF-b signaling, effectively well as following infectious and inflammatory diseases (2). Recent blocks albumin-induced brain TGF-b signaling and prevents ep- studies suggest that vascular injury, and specifically blood–brain ilepsy (16). barrier (BBB) dysfunction and the extravasation of serum albu- Although accumulating experimental data from animal models by guest on October 1, 2021 min, plays a key role in postinjury epilepsy (3–7) (for reviews, see strongly support a role for inflammatory responses in epilepto- Refs. 8, 9). genesis (17, 18), several important questions remain unanswered: Epileptic brains often show glial activation, which was suggested What triggers the epileptogenic inflammatory process? Which to play an important role in neuronal hyperexcitability (10), specific cell populations are involved? What inflammatory medi- synaptogenesis (11), and epileptogenesis (12, 13). Under BBB ators are critical to the epileptogenesis process? And what are the breakdown, serum albumin binds to TGF-bR2, activates TGF-b mechanisms by which inflammatory cytokines affect neuronal excitability? Because activation of TGF-b signaling in glial sub- sets has been implicated in both pro- and anti-inflammatory pro- *Shraga Segal Department of Microbiology, Immunology, and Genetics, Faculty of Health Sciences, Zlotowski Center for Neuroscience, Ben-Gurion University of the cesses (14, 19–25), this study aims to uncover the molecular and Negev, Beer-Sheva 84105, Israel; †Department of Physiology and Cell Biology, cellular mechanisms promoting a proinflammatory TGF-b1 sig- Faculty of Health Sciences, Zlotowski Center for Neuroscience, Ben-Gurion Univer- ‡ naling in non-neuronal populations and their potential role in the sity of the Negev, Beer-Sheva 84105, Israel: and Department of Medical Neurosci- ence, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia B3H 4R2, induction of epilepsy. Canada 1N.L. and D.Z.M. contributed equally to this work. Materials and Methods 2A.F. and A.M. contributed equally to this work as cosenior authors. Mice Received for publication June 5, 2014. Accepted for publication June 2, 2015. C57BL/6 mice were purchased from The Jackson Laboratory (Bar Harbor, This work was supported by Israel Science Foundation Grants 713/11 (to A.F.) and ME). FVB/N mice were purchased from Harlan Laboratories (Rehovot, 531/11 (to A.M.), German Israeli Foundation Grant 124/2008 (to A.F.), National Israel). Mice were bred and maintained in a local specific pathogen-free Institute for Neurological Disorders and Stroke Grant 1rO1N5066005 (to A.F.), animal facility. All surgical and experimental procedures were approved by European Union’s Seventh Framework Program FP7/2007–2013 Grant 602102 (EPI- the Institutional Animal Care and Use Committee of Ben-Gurion Uni- TARGET, to A.F.), and by a local institutional grant (Ben-Gurion University of the Negev, Faculty of Health) (to A.M. and A.F.). versity of the Negev, Israel. Address correspondence and reprint requests to Prof. Alon Monsonego, Ben-Gurion Cell culture University of the Negev, Faculty of Health Sciences, Beer-Sheva 84105, Israel. E-mail address: [email protected] Primary glial cultures were prepared from the cerebral cortex of 1-d-old Abbreviations used in this article: ACSF, artificial cerebrospinal fluid; BBB, blood– C57BL/6 mice as previously described (19). Briefly, cortices were ex- brain barrier; GFAP, glial fibrillary acidic protein; ICC, immunocytochemistry; ICV, cised, cleaned from meningeal tissues, and digested with 2.5% trypsin intracerebroventricular; qPCR, quantitative PCR. (solution C, Biological Industries, Beit Haemek, Israel) supplemented with 0.5 mg/ml DNase I (Worthington Biochemical, Lakewood, NJ) for 5 min at Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 37˚C. DNase I (5 mg/ml) was then added prior to passing the digested www.jimmunol.org/cgi/doi/10.4049/jimmunol.1401446 1714 TGF-b SIGNALING–INDUCED EPILEPTOGENESIS tissue through a thin pipette several times. The cells were then suspended Little Chalfont, U.K.] or anti-mouse [Jackson ImmunoResearch Labora- in DMEM (Life Technologies, Paisley, U.K.) supplemented with 10% FBS tories, West Grove, PA]) for 1.5 h at room temperature. Detection of im- (Thermo Fisher Scientific, Logan, UT), 4 mM L-glutamine, 100 U/ml munoreactive bands was carried out with ImageQuant LAS 4000 (GE penicillin, 1 mg/ml streptomycin, 2.5 U/ml nystatin, 10 mM HEPES, Healthcare Life Sciences) using ECL. 1 mM sodium pyruvate, 10 mM nonessential amino acids, and 50 mM 2-ME (all purchased from Biological Industries) and seeded onto poly-D-lysine Immunocytochemistry (Sigma-Aldrich, Jerusalem, Israel)–coated flasks and kept at 37˚C, 5% CO2 Primary glial cells or purified astrocytes were cultured on eight-well Lab- and 95% humidity. Growth medium was replenished after 24 h and every Tek culture slides (1.5 3 105 cells/well) treated with 10 ng/ml TGF-b1 for 2–3 d thereafter. The culture reaches confluence after 12–14 d and is then 1 h, fixed in 4% buffered paraformaldehyde for 15 min, washed in PBS, subjected to quantitative PCR (qPCR), ELISA, and Western blot analyses as and permeabilized in methanol for 10 min at 220˚C. After PBS washing, whole glia or purified cell subsets as described below. cells were blocked for 2 h at room temperature with Dyna Ab diluent (GBI Cell separation and flow cytometry Labs, Bothell, WA) and were then incubated for 24 h at 4˚C with primary anti-CD68 diluted 1:250 (BioLegend) or anti–glial fibrillary acidic protein Cell separation procedure was conducted according to the standard man- (GFAP) diluted 1:500 (Invitrogen) together with anti-SMAD2/3 and anti– ufacturer’s protocol. In brief, glial cells were harvested between days 14 p-SMAD3 diluted 1:200 (Cell Signaling Technologies). Anti-CNPase was and 20 of the culture using a 0.25% trypsin solution (solution A, Biological diluted 1:150 (Abcam). Cells were then washed with PBS and incubated Industries), washed, and incubated with PE-conjugated anti-CD11b mag- with Alexa Fluor 488, 546, or 633 Abs (Invitrogen) diluted 1:500. TO- netic beads (Stemcell Technologies, Vancouver, BC, Canada). Cells were PRO-3 (Invitrogen) diluted 1:1500 was used for counterstaining. All then placed onto a magnet for separation.
Load more

Recommended publications
  • Altered Protein Profiles During Epileptogenesis in the Pilocarpine
    ORIGINAL RESEARCH published: 28 May 2021 doi: 10.3389/fneur.2021.654606 Altered Protein Profiles During Epileptogenesis in the Pilocarpine Mouse Model of Temporal Lobe Epilepsy Md. Mahiuddin Ahmed 1, Andrew J. Carrel 2, Yasmin Cruz Del Angel 2, Jessica Carlsen 2, Ajay X. Thomas 2,3,4, Marco I. González 2, Katheleen J. Gardiner 5† and Amy Brooks-Kayal 2,6,7,8*† 1 Department of Neurology, University of Colorado Alzheimer’s and Cognition Center, Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, United States, 2 Division of Neurology and Translational Epilepsy Research Program, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, United States, 3 Section of Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States, 4 Section of Child Neurology, Texas Children’s Hospital, Houston, TX, United States, Edited by: 5 Department of Pediatrics, Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Kjell Heuser, Aurora, CO, United States, 6 Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Oslo University Hospital, Norway Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, United States, 7 Children’s Hospital Colorado, Reviewed by: Aurora, CO, United States, 8 Department of Neurology, University of California Davis School of Medicine, Sacramento, CA, Victor Rodrigues Santos, United States Federal University of Minas Gerais, Brazil Divya Vohora, Epilepsy is characterized by recurrent, spontaneous seizures and is a major contributor Jamia Hamdard University, India to the global burden of neurological disease. Although epilepsy can result from a variety *Correspondence: of brain insults, in many cases the cause is unknown and, in a significant proportion Amy Brooks-Kayal of cases, seizures cannot be controlled by available treatments.
    [Show full text]
  • Post Traumatic Epilepsy : a Review of Scientific Evidence
    Indian J Physiol Pharmacol 2006; 50 (1) : 7–16 REVIEW ARTICLE POST TRAUMATIC EPILEPSY : A REVIEW OF SCIENTIFIC EVIDENCE Y. K. GUPTA* AND MADHUR GUPTA Neuropharmacology Laboratory, Department of Pharmacology, All India Institute of Medical Sciences, New Delhi – 110 029 ( Received on July 15, 2005 ) Abstract : Post traumatic epilepsy is the development of recurrent seizures following head trauma and has a high clinical relevance. Several risk factors including some genetic factors increase the susceptibility of post traumatic epilepsy. The precise mechanisms of epileptogenesis in post-traumatic epilepsy are still poorly understood. Many structural, physiologic and biochemical changes in the brain may account for . epileptogenesis. The reactive oxygen species (ROS), especially OH and excitotoxicity are primarily involved. Antioxidants, like tocopherol, antiepileptic drug zonisamide, condensed tannins, melatonin, adenosine, trans-resveratrol, and some other agents have been proposed to prevent epileptogenic focus formation. The review also discusses various aspects of post traumatic epilepsy, mechanisms of epileptogenesis, and clinical implications. Key words : epilepsy trauma posttraumatic seizure oxidative stress INTRODUCTION recurrent epileptic seizures due to brain damage (2). It complicates the management Epilepsy is one of the most common of the head injuries patients by increasing neurological disorders affecting nearly 0.5 the intracranial pressure and altering percent of the world population (1). the level of unconsciousness. Among the Traumatic brain injury, which is a major long term complications of traumatic cause of morbidity and mortality world wide, brain injury, post traumatic epilepsy has been reported to be one of the major remains one of the most troubling and in risk factor for epileptic seizures.
    [Show full text]
  • Reactive Astrocyte-Driven Epileptogenesis Is Induced by Microglia Initially Activated Following Status Epilepticus
    Reactive astrocyte-driven epileptogenesis is induced by microglia initially activated following status epilepticus Fumikazu Sano, … , Masao Aihara, Schuichi Koizumi JCI Insight. 2021;6(9):e135391. https://doi.org/10.1172/jci.insight.135391. Research Article Neuroscience Graphical abstract Find the latest version: https://jci.me/135391/pdf RESEARCH ARTICLE Reactive astrocyte-driven epileptogenesis is induced by microglia initially activated following status epilepticus Fumikazu Sano,1,2,3 Eiji Shigetomi,1,3 Youichi Shinozaki,1,3 Haruka Tsuzukiyama,1 Kozo Saito,1,3,4 Katsuhiko Mikoshiba,5 Hiroshi Horiuchi,6 Dennis Lawrence Cheung,6 Junichi Nabekura,6 Kanji Sugita,2 Masao Aihara,2 and Schuichi Koizumi1,3 1Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, 2Department of Pediatrics, Faculty of Medicine, and 3Yamanashi GLIA Center, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi, Japan. 4Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan. 5Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China. 6Division of Homeostatic Development, National Institute for Physiological Sciences, Okazaki, Japan. Extensive activation of glial cells during a latent period has been well documented in various animal models of epilepsy. However, it remains unclear whether activated glial cells contribute to epileptogenesis, i.e., the chronically persistent process leading to epilepsy. Particularly, it is not clear whether interglial communication between different types of glial cells contributes to epileptogenesis, because past literature has mainly focused on one type of glial cell. Here, we show that temporally distinct activation profiles of microglia and astrocytes collaboratively contributed to epileptogenesis in a drug-induced status epilepticus model.
    [Show full text]
  • Epileptogenesis Causes Long-Term Plasticity Changes in Calbindin D-28K in the Rat Pilocarpine Model of Acquired Epilepsy
    Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2005 Epileptogenesis Causes Long-Term Plasticity Changes in Calbindin D-28k in the Rat Pilocarpine Model of Acquired Epilepsy Anne Johnston Harrison Virginia Commonwealth University Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Neurology Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/855 This Thesis is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. EPILEPTOGENESIS CAUSES LONG-TERM PLASTICITY CHANGES IN EXPRESSION OF CALBINDIN D-28K IN THE RAT PILOCARPINE MODEL OF ACQUIRED EPILEPSY A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science at Virginia Commonwealth University Anne Elizabeth Johnston Harrison Bachelor of Science in Pharmacy Virginia Commonwealth University May 1996 Bachelor of Science in Psychology The College of William and Mary May 1993 Director: Robert J. DeLorenzo, M.D., Ph.D., M.P.H. Professor Department of Neurology Virginia Convnonwealth University Richmond, Virginia December 2005 DEDICATION To my husband, Steve, for all of his encouragement, love, and support. Te amo mejo. ACKNOWLEDGEMENTS I would like to take this opportunity to thank a number of people without whom I could not have completed this thesis. Each of you has made immeasurable contributions to my education and personal growth. First, I must credit my family for their constant support, love, and encouragement in all of my endeavors, and for emphasizing the significance of continued learning throughout life.
    [Show full text]
  • Clinical Approach to Posttraumatic Epilepsy
    57 Clinical Approach to Posttraumatic Epilepsy Vikram R. Rao, MD, PhD1 Karen L. Parko, MD1,2 1 Department of Neurology, University of California, Address for correspondence Vikram R. Rao, MD, PhD, University of San Francisco, California California, San Francisco, Epilepsy Center, 400 Parnassus Ave, 8th 2 Department of Neurology, San Francisco Veterans Affairs Medical Floor, San Francisco, CA 94143 (e-mail: [email protected]). Center, San Francisco, California Semin Neurol 2015;35:57–63. Abstract Traumatic brain injury (TBI) is one of the most common causes of acquired epilepsy, and posttraumatic epilepsy (PTE) results in significant somatic and psychosocial morbidity. The risk of developing PTE relates directly to TBI severity, but the latency to first seizure can be decades after the inciting trauma. Given this “silent period,” much work has focused on identification of molecular and radiographic biomarkers for risk stratification and on development of therapies to prevent epileptogenesis. Clinical management requires vigilant neurologic surveillance and recognition of the heterogeneous endo- Keywords phenotypes associated with PTE. Appropriate treatment of patients who have or are at ► traumatic brain injury risk for seizures varies as a function of time after TBI, and the clinician’s armamentarium ► epilepsy includes an ever-expanding diversity of pharmacological and surgical options. Most ► posttraumatic recently, neuromodulation with implantable devices has emerged as a promising epilepsy therapeutic strategy for some patients with refractory PTE. Here, we review the ► seizure epidemiology, diagnostic considerations, and treatment options for PTE and develop ► neuromodulation a roadmap for providers encountering this challenging clinical entity. “…the brain may be injured by contusion, laceration, the wake of TBI.
    [Show full text]
  • A Brain-Heart Biomarker for Epileptogenesis
    This Accepted Manuscript has not been copyedited and formatted. The final version may differ from this version. Research Articles: Neurobiology of Disease A Brain-Heart Biomarker for Epileptogenesis Fatemeh Bahari1,2, Paddy Ssentongo1,2, Steven J. Schiff1,2,3,5,6 and Bruce J. Gluckman1,2,3,4 1Center for Neural Engineering, Pennsylvania State University, University Park, PA 16802, USA. 2Department of Engineering Science and Mechanics, Pennsylvania State University, University Park, PA 16802, USA. 3Department of Neurosurgery, Pennsylvania State College of Medicine, Hershey, PA 16802, USA. 4Department of Bioengineering, Pennsylvania State University, University Park, PA 16802, USA. 5Department of Physics, Pennsylvania State University, University Park, PA 16802, USA. 6Center for Infectious Disease Dynamics, Pennsylvania State University, University Park, PA 16802, USA. DOI: 10.1523/JNEUROSCI.1130-18.2018 Received: 1 May 2018 Revised: 17 July 2018 Accepted: 8 August 2018 Published: 27 August 2018 Author contributions: F.B., S.J.S., and B.J.G. designed research; F.B. and P.S. performed research; F.B. and B.J.G. analyzed data; F.B. wrote the first draft of the paper; F.B., S.J.S., and B.J.G. edited the paper; F.B. and B.J.G. wrote the paper. Conflict of Interest: The authors declare no competing financial interests. We thank Ali Nabi, Balaji Shanmugasundaram, and Myles W. Billard for assistance in development of the acquisition electronics and recording electrodes. This work was supported by Pennsylvania State Institute for the Neuroscience from Pennsylvania Department of Health Tobacco Funds, a Multidisciplinary grant from Citizens United for Research in Epilepsy (CURE), National Institute of Health grant R01EB019804, and a doctoral Academic Computing Fellowship from Pennsylvania State University to F.B.
    [Show full text]
  • Epileptogenesis and Epilepsy
    Epileptogenesis and Epilepsy Asla Pitkänen and Xavier Ekolle Ndode-Ekane A.I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland www.tocris.com The word “epilepsy” is derived from the Greek verb ἐπιλαμβάνειν (or epilambánein) meaning “to be seized”, “to be taken hold of”, or “to be attacked”. Hippocrates (400 BC) was the first to suggest that epilepsy is a Products available from Tocris disease of the brain that must be treated. According to the WHO, globally 60 million people have epilepsy, and an estimated 2.4 million are diagnosed with epilepsy each year. There are more than 20 anti-seizure drugs Ca2+-Activated Potassium Channels on market, but in about 30% of people with epilepsy, seizures are not controlled by medication. Apamin, 1-EBIO Ca2+-ATPase Paxilline, Thapsigargin Terminology Molecular, Cellular and Neuronal Network Pathologies CB1 Receptors ACEA, AM 251, (-)-Cannabidiol, Seizure A transient occurrence of signs and/or symptoms due to abnormal excessive Epileptogenesis can be initiated, for example, by an “epilepsy gene”, various types of acute SR141716A or synchronous neuronal activity in the brain. Seizures are categorized according to brain insults or chronic neurodegenerative diseases. The entire epileptogenic process is Cyclooxygenase the International League Against Epilepsy (ILAE) classification into three types: modulated by an individual’s genetic background, microbiota, and exposome (non-genetic Celecoxib, Resveratrol generalized onset; focal onset (previously known as partial seizures); and unknown exposures of an individual in a lifetime, e.g., life-style, medications etc.). Epileptogenesis Gap Channels onset. Epilepsy gene Genetic background continues after epilepsy diagnosis (i.e., occurrence of the first unprovoked seizure) and leads Gap19 to various outcomes (SUDEP, sudden unexpected death; QoL, quality-of-life; Rx, treatment).
    [Show full text]
  • Physiological and Structural Evidence for Hippocampal Involvement in Persistent Seizure Susceptibility After Traumatic Brain Injury
    The Journal of Neuroscience, November 1, 2001, 21(21):8523–8537 Physiological and Structural Evidence for Hippocampal Involvement in Persistent Seizure Susceptibility after Traumatic Brain Injury Golijeh Golarai,1,2 Anders C. Greenwood,1,2 Dennis M. Feeney,1,2 and John A. Connor1 1Department of Neurosciences, University of New Mexico, Albuquerque, New Mexico 87131-5223, and 2Department of Psychology, University of New Mexico, Albuquerque, New Mexico 87133-5223 Epilepsy is a common outcome of traumatic brain injury (TBI), GABAA antagonists during field-potential and optical record- but the mechanisms of posttraumatic epileptogenesis are ings in hippocampal slices 3 and 15 weeks after TBI, we poorly understood. One clue is the occurrence of selective unmasked a persistent, abnormal APV-sensitive hyperexcitabil- hippocampal cell death after fluid-percussion TBI in rats, con- ity that was bilateral and localized to the granule cell and sistent with the reported reduction of hippocampal volume molecular layers of the DG. Finally, using Timm histochemistry, bilaterally in humans after TBI and resembling hippocampal we detected progressive sprouting of mossy fibers into the sclerosis, a hallmark of temporal-lobe epilepsy. Other features inner molecular layers of the DG bilaterally 2–27 weeks after of temporal-lobe epilepsy, such as long-term seizure suscepti- TBI. These findings are consistent with the development of bility, persistent hyperexcitability in the dentate gyrus (DG), and posttraumatic epilepsy in an animal model of impact head mossy fiber synaptic reorganization, however, have not been injury, showing a striking similarity to the enduring behavioral, examined after TBI. To determine whether TBI induces these functional, and structural alterations associated with temporal- changes, we used a well studied model of TBI by weight drop lobe epilepsy.
    [Show full text]
  • Microglial Mtor Is Neuronal Protective and Anti-Epileptogenic in the Pilocarpine Model of Temporal Lobe Epilepsy
    Research Articles: Cellular/Molecular Microglial mTOR is neuronal protective and anti-epileptogenic in the pilocarpine model of temporal lobe epilepsy https://doi.org/10.1523/JNEUROSCI.2754-19.2020 Cite as: J. Neurosci 2020; 10.1523/JNEUROSCI.2754-19.2020 Received: 19 November 2019 Revised: 5 August 2020 Accepted: 24 August 2020 This Early Release article has been peer-reviewed and accepted, but has not been through the composition and copyediting processes. The final version may differ slightly in style or formatting and will contain links to any extended data. Alerts: Sign up at www.jneurosci.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Copyright © 2020 the authors 1 Title: Microglial mTOR is neuronal protective and anti-epileptogenic in the pilocarpine 2 model of temporal lobe epilepsy. 3 4 Abbreviated title: Microglial mTOR in neuronal loss and epilepsy 5 Xiao-Feng Zhao1,5, *, Yuan Liao2, *, Mahabub Maraj Alam1, Ramkumar Mathur2, Paul Feustel1, 6 Joseph E. Mazurkiewicz1, Matthew A. Adamo3, Xinjun Cindy Zhu2, 4, Yunfei Huang1, 5 7 8 1. Department of Neuroscience and Experimental Therapeutics, Albany Medical College, 9 Albany, New York 12208 10 2. Department of Molecular and Cellular Physiology, Albany Medical College, Albany, New 11 York 12208 12 3. Department of Neurosurgery, Albany Medical College, Albany, New York 12208 13 4. Department of Medicine, Albany Medical College, Albany, New York, 12208 14 5. Lead contact/correspondence: [email protected]; [email protected] 15 * Authors share co-first authorship. 16 17 Number of pages: 36 18 Number of figures: 9 19 Number of tables: 2 20 Number of multimedia: 0 21 Number of words for abstract: 149 22 Number of words for introduction: 701 23 Number of words for discussion: 1843 24 25 Conflict of interest statement: The authors declare no competing financial interests.
    [Show full text]
  • Reactive Astrocyte-Driven Epileptogenesis Is Induced by Microglia Initially Activated Following Status Epilepticus
    Reactive astrocyte-driven epileptogenesis is induced by microglia initially activated following status epilepticus Fumikazu Sano, … , Masao Aihara, Schuichi Koizumi JCI Insight. 2021. https://doi.org/10.1172/jci.insight.135391. Research In-Press Preview Neuroscience Graphical abstract Find the latest version: https://jci.me/135391/pdf 1 Reactive astrocyte-driven epileptogenesis is induced by microglia initially 2 activated following status epilepticus 3 4 Fumikazu Sano1,2, 3, Eiji Shigetomi1,3, Youichi Shinozaki1,3, Haruka 5 Tsuzukiyama1, Kozo Saito1,3,4, Katsuhiko Mikoshiba5, Hiroshi Horiuchi 6, Dennis 6 Lawrence Cheung6, Junichi Nabekura6, Kanji Sugita2, Masao Aihara2, Schuichi 7 Koizumi1,3* 8 9 1 Department of Neuropharmacology, Interdisciplinary Graduate School of 10 Medicine, University of Yamanashi, Yamanashi, Japan, 11 2 Department of Pediatrics, Faculty of Medicine, University of Yamanashi, 12 Yamanashi, Japan, 13 3 GLIA Center, Interdisciplinary Graduate School of Medicine, University of 14 Yamanashi, Yamanashi, Japan, 15 4 Department of Neurology, Graduate School of Medical Science, Kyoto 16 Prefectural University of Medicine, Kyoto, Japan, 17 5 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech 18 University, Shanghai, China 1 19 6 Division of Homeostatic Development, National Institute for Physiological 20 Sciences, Okazaki, Japan 21 22 *Corresponding Author: Schuichi Koizumi, University of Yamanashi, 1110 Chuo, 23 Yamanashi, 409-3898, Japan. 24 Phone: +81-55-273- 9503; Email: [email protected]. 25 26 Conflicts of interest: The authors have declared that no conflict of interest 27 exists. 28 2 29 Abstract 30 Extensive activation of glial cells during a latent period has been well 31 documented in various animal models of epilepsy. However, it remains unclear 32 whether activated glial cells contribute to epileptogenesis; i.e., the chronically 33 persistent process leading to epilepsy.
    [Show full text]
  • Incidence and Risk Factors of Posttraumatic Seizures Following Traumatic Brain Injury: a Traumatic Brain Injury Model Systems Study 1,2Anne C
    FULL-LENGTH ORIGINAL RESEARCH Incidence and risk factors of posttraumatic seizures following traumatic brain injury: A Traumatic Brain Injury Model Systems Study 1,2Anne C. Ritter, 2,3,4,5Amy K. Wagner, 1Anthony Fabio, 6,7Mary Jo Pugh, 8William C. Walker, 9Jerzy P. Szaflarski, 10Ross D. Zafonte, 11Allen W. Brown, 12,13Flora M. Hammond, 14Tamara Bushnik, 15Douglas Johnson-Greene, 16Timothy Shea, 17Jason W. Krellman, 16Joseph A. Rosenthal, and 18Laura E. Dreer Epilepsia, **(*):1–10, 2016 doi: 10.1111/epi.13582 SUMMARY Objective: Determine incidence of posttraumatic seizure (PTS) following traumatic brain injury (TBI) among individuals with moderate-to-severe TBI requiring rehabili- tation and surviving at least 5 years. Methods: Using the prospective TBI Model Systems National Database, we calculated PTS incidence during acute hospitalization, and at years 1, 2, and 5 postinjury in a con- tinuously followed cohort enrolled from 1989 to 2000 (n = 795). Incidence rates were stratified by risk factors, and adjusted relative risk (RR) was calculated. Late PTS associations with immediate (<24 h), early (24 h–7 day), or late seizures (>7 day) versus no seizure prior to discharge from acute hospitalization was also examined. Results: PTS incidence during acute hospitalization was highest immediately (<24 h) post-TBI (8.9%). New onset PTS incidence was greatest between discharge from inpa- tient rehabilitation and year 1 (9.2%). Late PTS cumulative incidence from injury to year 1 was 11.9%, and reached 20.5% by year 5. Immediate/early PTS RR (2.04) was Anne Ritter recently increased for those undergoing surgical evacuation procedures. Late PTS RR was sig- received her doctorate nificantly greater for individuals who self-identified as a race other than black/white = = in neuroepidemiology (year 1 RR 2.22), and for black individuals (year 5 RR 3.02) versus white individuals.
    [Show full text]
  • Reactive Glia Inflammatory Signaling Pathways and Epilepsy
    International Journal of Molecular Sciences Review Reactive Glia Inflammatory Signaling Pathways and Epilepsy Pascual Sanz 1,* and Maria Adelaida Garcia-Gimeno 2 1 Instituto de Biomedicina de Valencia (CSIC) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Jaime Roig 11, 46010 Valencia, Spain 2 Department of Biotechnology, Escuela Técnica Superior de Ingeniería Agronómica y del Medio Natural (ETSIAMN), Universitat Politècnica de València, 46022 Valencia, Spain; [email protected] * Correspondence: [email protected]; Tel.: +34-963391779; Fax: +34-963690800 Received: 21 May 2020; Accepted: 6 June 2020; Published: 8 June 2020 Abstract: Neuroinflammation and epilepsy are interconnected. Brain inflammation promotes neuronal hyper-excitability and seizures, and dysregulation in the glia immune-inflammatory function is a common factor that predisposes or contributes to the generation of seizures. At the same time, acute seizures upregulate the production of pro-inflammatory cytokines in microglia and astrocytes, triggering a downstream cascade of inflammatory mediators. Therefore, epileptic seizures and inflammatory mediators form a vicious positive feedback loop, reinforcing each other. In this work, we have reviewed the main glial signaling pathways involved in neuroinflammation, how they are affected in epileptic conditions, and the therapeutic opportunities they offer to prevent these disorders. Keywords: inflammation; signaling pathways; epilepsy; reactive astrocytes; microglia 1. Introduction Epilepsy is a neurological disorder characterized by a predisposition to generate recurrent epileptic seizures and the associated cognitive, psychological, and social consequences [1]. Epilepsy affects 1% of the total world population (around 65 million people worldwide) and it is caused by acquired insults in the brain (e.g., after stroke or traumatic brain injury), infectious diseases, autoimmune diseases, and genetic mutations [1,2].
    [Show full text]