A systems-level analysis highlights microglial activation as a modifying factor in common epilepsies.

Animals Brain Endothelial Cells Epilepsy / metabolism Mice Microglia / metabolism Seizures
MRI cortical thinning gene expression post mortem

Journal

Neuropathology and applied neurobiology
ISSN: 1365-2990
Titre abrégé: Neuropathol Appl Neurobiol
Pays: England
ID NLM: 7609829

Informations de publication

Date de publication:
02 2022
Historique:
received: 31 03 2021
accepted: 15 07 2021
pubmed: 14 8 2021
medline: 8 4 2022
entrez: 13 8 2021
Statut: ppublish

Résumé

The causes of distinct patterns of reduced cortical thickness in the common human epilepsies, detectable on neuroimaging and with important clinical consequences, are unknown. We investigated the underlying mechanisms of cortical thinning using a systems-level analysis. Imaging-based cortical structural maps from a large-scale epilepsy neuroimaging study were overlaid with highly spatially resolved human brain gene expression data from the Allen Human Brain Atlas. Cell-type deconvolution, differential expression analysis and cell-type enrichment analyses were used to identify differences in cell-type distribution. These differences were followed up in post-mortem brain tissue from humans with epilepsy using Iba1 immunolabelling. Furthermore, to investigate a causal effect in cortical thinning, cell-type-specific depletion was used in a murine model of acquired epilepsy. We identified elevated fractions of microglia and endothelial cells in regions of reduced cortical thickness. Differentially expressed genes showed enrichment for microglial markers and, in particular, activated microglial states. Analysis of post-mortem brain tissue from humans with epilepsy confirmed excess activated microglia. In the murine model, transient depletion of activated microglia during the early phase of the disease development prevented cortical thinning and neuronal cell loss in the temporal cortex. Although the development of chronic seizures was unaffected, the epileptic mice with early depletion of activated microglia did not develop deficits in a non-spatial memory test seen in epileptic mice not depleted of microglia. These convergent data strongly implicate activated microglia in cortical thinning, representing a new dimension for concern and disease modification in the epilepsies, potentially distinct from seizure control.

Identifiants

DOI: 10.1111/nan.12758 PMID: 34388852 PMC: PMC8983060
pubmed: 34388852
doi: 10.1111/nan.12758
pmc: PMC8983060
mid: NIHMS1790382
doi:

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

e12758

Subventions

Organisme : Medical Research Council Clinician Scientist Fellowship
ID : MR/N008324/1
Organisme : NINDS NIH HHS
ID : R21 NS107739
Pays : United States
Organisme : Medical Research Council
ID : MR/L016311/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N008324/1
Pays : United Kingdom
Organisme : NIBIB NIH HHS
ID : U54 EB020403
Pays : United States
Organisme : NIH HHS
ID : R01 NS065838
Pays : United States
Organisme : NIH HHS
ID : S10 OD023696
Pays : United States
Organisme : NIBIB NIH HHS
ID : R01 EB015611
Pays : United States
Organisme : NIH HHS
ID : R01 NS097719
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS122827
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS065838
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS097719
Pays : United States
Organisme : NIH HHS
ID : U54 EB020403
Pays : United States

Commentaires et corrections

Type : CommentIn

Informations de copyright

© 2021 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.

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Auteurs

Andre Altmann (A)

Centre for Medical Image Computing, University College London, London, UK.
ORCID: 0000-0002-9265-2393

Mina Ryten (M)

Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.

Martina Di Nunzio (M)

Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Teresa Ravizza (T)

Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Daniele Tolomeo (D)

Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Regina H Reynolds (RH)

Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.

Alyma Somani (A)

Division of Neuropathology, UCL Queen Square Institute of Neurology, London, UK.

Marco Bacigaluppi (M)

Department of Neurology, San Raffaele Scientific Institute and Vita Salute San Raffaele University, Milan, Italy.

Valentina Iori (V)

Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Edoardo Micotti (E)

Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Rossella Di Sapia (R)

Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
ORCID: 0000-0001-7481-5198

Milica Cerovic (M)

Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Eleonora Palma (E)

Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy.

Gabriele Ruffolo (G)

Department of Physiology and Pharmacology, Sapienza University of Rome, Rome, Italy.

Juan A Botía (JA)

Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.
Departamento de Ingeniería de la Información y las Comunicaciones, Universidad de Murcia, Murcia, Spain.

Julie Absil (J)

Department of Radiology, Hôpital Erasme, Universite Libre de Bruxelles, Brussels, Belgium.

Saud Alhusaini (S)

Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
Neurology Department, Yale University School of Medicine, New Haven, CT, USA.

Marina K M Alvim (MKM)

Department of Neurology, University of Campinas, Campinas, Brazil.

Pia Auvinen (P)

Epilepsy Center, Department of Neurology, Kuopio University, Kuopio, Finland.
Institute of Clinical Medicine, Neurology, University of Eastern Finland, Kuopio, Finland.

Nuria Bargallo (N)

Magnetic Resonance Image Core Facility, IDIBAPS, Barcelona, Spain.
Centre de Diagnostic Per la Imatge (CDIC), Hospital Clinic, Barcelona, Spain.

Emanuele Bartolini (E)

Pediatric Neurology Unit, Children's Hospital A. Meyer-University of Florence, Florence, Italy.
Neurology Unit, USL Centro Toscana, Nuovo Ospedale Santo Stefano, Prato, Italy.

Benjamin Bender (B)

Department of Diagnostic and Interventional Neuroradiology, University of Tübingen, Tübingen, Germany.
ORCID: 0000-0002-3205-4631

Felipe P G Bergo (FPG)

Department of Neurology, University of Campinas, Campinas, Brazil.

Tauana Bernardes (T)

Department of Neurology, University of Campinas, Campinas, Brazil.

Andrea Bernasconi (A)

Neuroimaging of Epilepsy Laboratory, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.

Neda Bernasconi (N)

Neuroimaging of Epilepsy Laboratory, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.

Boris C Bernhardt (BC)

Multimodal Imaging and Connectome Analysis Lab, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.

Karen Blackmon (K)

Psychiatry and Psychology, Mayo Clinic, Jacksonville, FL, USA.

Barbara Braga (B)

Department of Neurology, University of Campinas, Campinas, Brazil.

Maria Eugenia Caligiuri (ME)

Neuroscience Research Center, Department of Medical and Surgical Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy.

Anna Calvo (A)

Magnetic Resonance Image Core Facility, IDIBAPS, Barcelona, Spain.

Chad Carlson (C)

Comprehensive Epilepsy Center, Department of Neurology, New York University School of Medicine, New York, New York, USA.
Department of Neurology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.

Sarah J A Carr (SJA)

Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Gianpiero L Cavalleri (GL)

Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
FutureNeuro Research Centre, RCSI, Dublin, Ireland.

Fernando Cendes (F)

Department of Neurology, University of Campinas, Campinas, Brazil.

Jian Chen (J)

Department of Computer Science and Engineering, The Ohio State University, Columbus, Ohio, USA.

Shuai Chen (S)

Cognitive Science Department, Xiamen University, Xiamen, China.
Fujian Key Laboratory of the Brain-like Intelligent Systems, Xiamen, China.

Andrea Cherubini (A)

Neuroscience Research Center, Department of Medical and Surgical Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy.

Luis Concha (L)

Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, Mexico.

Philippe David (P)

Department of Radiology, Hôpital Erasme, Universite Libre de Bruxelles, Brussels, Belgium.

Norman Delanty (N)

Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
FutureNeuro Research Centre, RCSI, Dublin, Ireland.
Division of Neurology, Beaumont Hospital, Dublin 9, Ireland.

Chantal Depondt (C)

Department of Neurology, Hôpital Erasme, Universite Libre de Bruxelles, Brussels, Belgium.

Orrin Devinsky (O)

Department of Neurology, Langone School of Medicine, New York University, New York, NY, USA.

Colin P Doherty (CP)

FutureNeuro Research Centre, RCSI, Dublin, Ireland.
School of Medicine, Trinity College Dublin, Dublin, Ireland.

Martin Domin (M)

Functional Imaging Unit, Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany.

Niels K Focke (NK)

Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
Department of Clinical Neurophysiology, University Medicine Göttingen, Göttingen, Germany.

Sonya Foley (S)

The Welsh Epilepsy Unit, Department of Neurology, University Hospital of Wales, Cardiff, UK.

Wendy Franca (W)

Department of Neurology, University of Campinas, Campinas, Brazil.

Antonio Gambardella (A)

Neuroscience Research Center, Department of Medical and Surgical Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy.
Institute of Neurology, University "Magna Graecia", Catanzaro, Italy.

Renzo Guerrini (R)

Pediatric Neurology Unit, Children's Hospital A. Meyer-University of Florence, Florence, Italy.

Khalid Hamandi (K)

The Welsh Epilepsy Unit, Department of Neurology, University Hospital of Wales, Cardiff, UK.
Cardiff University Brain Research Imaging Centre, School of Psychology, Cardiff University, Cardiff, UK.

Derrek P Hibar (DP)

Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Los Angeles, California, USA.

Dmitry Isaev (D)

Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Los Angeles, California, USA.

Graeme D Jackson (GD)

The Florey Institute of Neuroscience and Mental Health, Austin Campus, Melbourne, Victoria, Australia.
Florey Department of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia.

Neda Jahanshad (N)

Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Los Angeles, California, USA.

Reetta Kälviäinen (R)

Epilepsy Center, Department of Neurology, Kuopio University, Kuopio, Finland.
Institute of Clinical Medicine, Neurology, University of Eastern Finland, Kuopio, Finland.

Simon S Keller (SS)

Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.

Peter Kochunov (P)

Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, Maryland, USA.

Raviteja Kotikalapudi (R)

Department of Diagnostic and Interventional Neuroradiology, University of Tübingen, Tübingen, Germany.
Functional Imaging Unit, Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany.
Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.

Magdalena A Kowalczyk (MA)

The Florey Institute of Neuroscience and Mental Health, Austin Campus, Melbourne, Victoria, Australia.

Ruben Kuzniecky (R)

Department of Neurology, Zucker Hofstra School of Medicine, New York, New York, USA.

Patrick Kwan (P)

Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia.

Angelo Labate (A)

Neuroscience Research Center, Department of Medical and Surgical Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy.
Institute of Neurology, University "Magna Graecia", Catanzaro, Italy.

Soenke Langner (S)

Functional Imaging Unit, Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald, Germany.

Matteo Lenge (M)

Pediatric Neurology Unit, Children's Hospital A. Meyer-University of Florence, Florence, Italy.

Min Liu (M)

Neuroimaging of Epilepsy Laboratory, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.

Pascal Martin (P)

Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.

Mario Mascalchi (M)

"Mario Serio" Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.

Stefano Meletti (S)

Department of Biomedical, Metabolic, and Neural Science, University of Modena and Reggio Emilia, NOCSE Hospital, Modena, Italy.

Marcia E Morita-Sherman (ME)

Department of Neurology, University of Campinas, Campinas, Brazil.
Cleveland Clinic Neurological Institute, Cleveland, USA.

Terence J O'Brien (TJ)

Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia.
The Department of Medicine (The Royal Melbourne Hospital), The University of Melbourne, Parkville, Victoria, Australia.

Jose C Pariente (JC)

Magnetic Resonance Image Core Facility, IDIBAPS, Barcelona, Spain.

Mark P Richardson (MP)

Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Department of Neurology, King's College Hospital, London, UK.

Raul Rodriguez-Cruces (R)

Multimodal Imaging and Connectome Analysis Lab, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada.
Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, Mexico.

Christian Rummel (C)

Support Center for Advanced Neuroimaging (SCAN), University Institute for Diagnostic and Interventional Neuroradiology, Inselspital, University of Bern, Bern, Switzerland.

Taavi Saavalainen (T)

Institute of Clinical Medicine, Neurology, University of Eastern Finland, Kuopio, Finland.
Medical Imaging Unit, Central Finland Central Hospital, Jyväskylä, Finland.

Mira K Semmelroch (MK)

The Florey Institute of Neuroscience and Mental Health, Austin Campus, Melbourne, Victoria, Australia.
Florey Department of Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia.

Mariasavina Severino (M)

Neuroradiology Unit, Department of Head and Neck and Neurosciences, Istituto Giannina Gaslini, Genoa, Italy.
ORCID: 0000-0003-4730-5322

Pasquale Striano (P)

Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy.

Thomas Thesen (T)

Comprehensive Epilepsy Center, Department of Neurology, New York University School of Medicine, New York, New York, USA.

Rhys H Thomas (RH)

Institute of Translational and Clinical Research, Newcastle University, Newcastle upon Tyne, UK.

Manuela Tondelli (M)

Cleveland Clinic Neurological Institute, Cleveland, USA.

Domenico Tortora (D)

Neuroradiology Unit, Department of Head and Neck and Neurosciences, Istituto Giannina Gaslini, Genoa, Italy.

Anna Elisabetta Vaudano (AE)

Department of Biomedical, Metabolic, and Neural Science, University of Modena and Reggio Emilia, NOCSE Hospital, Modena, Italy.

Lucy Vivash (L)

Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia.
Melbourne Brain Centre, Department of Medicine, University of Melbourne, Parkville, Victoria, Australia.

Felix von Podewils (F)

Department of Neurology, University Medicine Greifswald, Greifswald, Germany.

Jan Wagner (J)

Department of Neurology, University of Ulm and Universitäts- and Rehabilitationskliniken Ulm, Ulm, Germany.

Bernd Weber (B)

Institute of Experimental Epileptology and Cognition Research, University of Bonn, Bonn, Germany.

Roland Wiest (R)

Support Center for Advanced Neuroimaging (SCAN), University Institute for Diagnostic and Interventional Neuroradiology, Inselspital, University of Bern, Bern, Switzerland.

Clarissa L Yasuda (CL)

Department of Neurology, University of Campinas, Campinas, Brazil.

Guohao Zhang (G)

Department of Computer Science and Electrical Engineering, University of Maryland, Baltimore County, Baltimore, Maryland, USA.

Junsong Zhang (J)

Cognitive Science Department, Xiamen University, Xiamen, China.
Fujian Key Laboratory of the Brain-like Intelligent Systems, Xiamen, China.

Costin Leu (C)

Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK.

Andreja Avbersek (A)

Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.

Maria Thom (M)

Division of Neuropathology, UCL Queen Square Institute of Neurology, London, UK.
Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK.
ORCID: 0000-0001-7712-2629

Christopher D Whelan (CD)

Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland.
Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Los Angeles, California, USA.

Paul Thompson (P)

Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Los Angeles, California, USA.

Carrie R McDonald (CR)

Multimodal Imaging Laboratory, University of California San Diego, San Diego, California, USA.
Department of Psychiatry, University of California San Diego, San Diego, California, USA.

Annamaria Vezzani (A)

Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Sanjay M Sisodiya (SM)

Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, UK.
Chalfont Centre for Epilepsy, Bucks, UK.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › A systems-level analysis highlights microglial...
questionsmedicales.fr › Système nerveux › Système nerveux central › Encéphale › A systems-level analysis highlights microglial...
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules endothéliales › A systems-level analysis highlights microglial...
questionsmedicales.fr › Maladies du système nerveux › Maladies du système nerveux central › Encéphalopathies › Épilepsie › A systems-level analysis highlights microglial...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › A systems-level analysis highlights microglial...
questionsmedicales.fr › Cellules › Névroglie › Microglie › A systems-level analysis highlights microglial...
questionsmedicales.fr › États, signes et symptômes pathologiques › Signes et symptômes › Manifestations neurologiques › Crises épileptiques › A systems-level analysis highlights microglial...