ParkinsonCanadaV1, Pmc, Curation, bibRecord, 000798

GRK2 and group I mGluR mediate inflammation-induced sensitization to excitotoxic neurodegeneration

Identifieur interne : 000798 ( Pmc/Curation ); précédent : 000797; suivant : 000799

GRK2 and group I mGluR mediate inflammation-induced sensitization to excitotoxic neurodegeneration

Auteurs : Vincent Degos [France, États-Unis] ; Stéphane Peineau [France, Royaume-Uni] ; Cora Nijboer [Pays-Bas] ; Angela M. Kaindl [France] ; Stéphanie Sigaut [France] ; Géraldine Favrais [France] ; Frank Plaisant [France] ; Natacha Teissier [France] ; Elodie Gouadon [France] ; Alain Lombet [France] ; Elie Saliba [France] ; Graham L. Collingridge [Royaume-Uni, Canada, Corée du Sud] ; Mervyn Maze [États-Unis] ; Ferdinando Nicoletti [Italie] ; Cobi Heijnen [Pays-Bas] ; Jean Mantz [France] ; Annemieke Kavelaars [Pays-Bas, États-Unis] ; Pierre Gressens [France, Royaume-Uni]

Source :

Annals of neurology [ 0364-5134 ] ; 2013.

RBID : PMC:3837433

Abstract

Objectives

The concept of inflammation-induced sensitization is emerging in the field of perinatal brain injury, stroke, Alzheimer disease and multiple sclerosis. However, mechanisms underpinning this process remain unidentified.

Methods

We combined in vivo systemic lipopolysaccharide (LPS) or Interleukin-1β (IL-1β) induced sensitization of neonatal and adult rodent cortical neurons to excitotoxic neurodegeneration with in vitro IL-1β sensitization of human and rodent neurons to excitotoxic neurodegeneration. Within these inflammation-induced sensitization models we assessed metabotropic glutamatergic receptor (mGluR) signaling and regulation.

Results

We demonstrate for the first time that group I mGluRs mediate inflammation-induced sensitization to neuronal excitotoxicity in neonatal and adult neurons across species. Inflammation induced G protein–coupled receptor kinase 2 (GRK2) down-regulation and genetic deletion of GRK2 mimicked the sensitizing effect of inflammation on excitotoxic neurodegeneration. Thus, we identify GRK2 as a potential molecular link between inflammation and mGluR-mediated sensitization.

Interpretation

Collectively, our findings indicate that inflammation-induced sensitization is universal across species and ages and that group I mGluRs and GRK2 represent new avenues for neuroprotection in perinatal and adult neurological disorders.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837433

DOI: 10.1002/ana.23868
PubMed: 23494575
PubMed Central: 3837433

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<author><name sortKey="Kavelaars, Annemieke" sort="Kavelaars, Annemieke" uniqKey="Kavelaars A" first="Annemieke" last="Kavelaars">Annemieke Kavelaars</name>
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<affiliation wicri:level="1"><nlm:aff id="A17">Centre for the Developing Brain, King's College, St Thomas' Campus, London, UK</nlm:aff>
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</affiliation>
</author>
<author><name sortKey="Sigaut, Stephanie" sort="Sigaut, Stephanie" uniqKey="Sigaut S" first="Stéphanie" last="Sigaut">Stéphanie Sigaut</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Inserm, U676, Hôpital Robert Debré, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Inserm, U676, Hôpital Robert Debré, Paris</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">Univ Paris Diderot, Sorbonne Paris Cité, UMRS 676, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Univ Paris Diderot, Sorbonne Paris Cité, UMRS 676, Paris</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A3">PremUP, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>PremUP, Paris</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Favrais, Geraldine" sort="Favrais, Geraldine" uniqKey="Favrais G" first="Géraldine" last="Favrais">Géraldine Favrais</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Inserm, U676, Hôpital Robert Debré, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Inserm, U676, Hôpital Robert Debré, Paris</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">Univ Paris Diderot, Sorbonne Paris Cité, UMRS 676, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Univ Paris Diderot, Sorbonne Paris Cité, UMRS 676, Paris</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A3">PremUP, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>PremUP, Paris</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Plaisant, Frank" sort="Plaisant, Frank" uniqKey="Plaisant F" first="Frank" last="Plaisant">Frank Plaisant</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Inserm, U676, Hôpital Robert Debré, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Inserm, U676, Hôpital Robert Debré, Paris</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">Univ Paris Diderot, Sorbonne Paris Cité, UMRS 676, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Univ Paris Diderot, Sorbonne Paris Cité, UMRS 676, Paris</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A3">PremUP, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>PremUP, Paris</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Teissier, Natacha" sort="Teissier, Natacha" uniqKey="Teissier N" first="Natacha" last="Teissier">Natacha Teissier</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Inserm, U676, Hôpital Robert Debré, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Inserm, U676, Hôpital Robert Debré, Paris</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">Univ Paris Diderot, Sorbonne Paris Cité, UMRS 676, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Univ Paris Diderot, Sorbonne Paris Cité, UMRS 676, Paris</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A3">PremUP, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>PremUP, Paris</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Gouadon, Elodie" sort="Gouadon, Elodie" uniqKey="Gouadon E" first="Elodie" last="Gouadon">Elodie Gouadon</name>
<affiliation wicri:level="1"><nlm:aff id="A7">Inserm, UMR 999, Labex LERMIT, Le Plessis-Robinson, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Inserm, UMR 999, Labex LERMIT, Le Plessis-Robinson</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A8">Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A9">Université Paris-Sud, Faculté de Médecine, Le Kremlin-Bicêtre, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Université Paris-Sud, Faculté de Médecine, Le Kremlin-Bicêtre</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Lombet, Alain" sort="Lombet, Alain" uniqKey="Lombet A" first="Alain" last="Lombet">Alain Lombet</name>
<affiliation wicri:level="1"><nlm:aff id="A7">Inserm, UMR 999, Labex LERMIT, Le Plessis-Robinson, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Inserm, UMR 999, Labex LERMIT, Le Plessis-Robinson</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A9">Université Paris-Sud, Faculté de Médecine, Le Kremlin-Bicêtre, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Université Paris-Sud, Faculté de Médecine, Le Kremlin-Bicêtre</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Saliba, Elie" sort="Saliba, Elie" uniqKey="Saliba E" first="Elie" last="Saliba">Elie Saliba</name>
<affiliation wicri:level="1"><nlm:aff id="A10">Inserm, U930, Université François Rabelais de Tours, Tours, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Inserm, U930, Université François Rabelais de Tours, Tours</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Collingridge, Graham L" sort="Collingridge, Graham L" uniqKey="Collingridge G" first="Graham L." last="Collingridge">Graham L. Collingridge</name>
<affiliation wicri:level="1"><nlm:aff id="A5">MRC Centre for Synaptic Plasticity, School of Physiology and Pharmacology, Medical Sciences Building, Bristol, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>MRC Centre for Synaptic Plasticity, School of Physiology and Pharmacology, Medical Sciences Building, Bristol</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A11">Brain Research Centre, Department of Psychiatry, University of British Columbia, Vancouver, Canada</nlm:aff>
<country xml:lang="fr">Canada</country>
<wicri:regionArea>Brain Research Centre, Department of Psychiatry, University of British Columbia, Vancouver</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A12">Department of Brain and Cognitive Sciences, Seoul National University, Seoul, Korea</nlm:aff>
<country xml:lang="fr">Corée du Sud</country>
<wicri:regionArea>Department of Brain and Cognitive Sciences, Seoul National University, Seoul</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Maze, Mervyn" sort="Maze, Mervyn" uniqKey="Maze M" first="Mervyn" last="Maze">Mervyn Maze</name>
<affiliation wicri:level="1"><nlm:aff id="A4">Department of Anesthesia and Perioperative Care, University of California, San Francisco, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Anesthesia and Perioperative Care, University of California, San Francisco</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Nicoletti, Ferdinando" sort="Nicoletti, Ferdinando" uniqKey="Nicoletti F" first="Ferdinando" last="Nicoletti">Ferdinando Nicoletti</name>
<affiliation wicri:level="1"><nlm:aff id="A13">Dept. of Physiology and Pharmacology, University of Rome Sapienza, Italy</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>Dept. of Physiology and Pharmacology, University of Rome Sapienza</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A14">IRCCS Neuromed, Pozzilli (IS), Italy</nlm:aff>
<country xml:lang="fr">Italie</country>
<wicri:regionArea>IRCCS Neuromed, Pozzilli (IS)</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Heijnen, Cobi" sort="Heijnen, Cobi" uniqKey="Heijnen C" first="Cobi" last="Heijnen">Cobi Heijnen</name>
<affiliation wicri:level="1"><nlm:aff id="A6">Laboratory for Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Laboratory for Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Mantz, Jean" sort="Mantz, Jean" uniqKey="Mantz J" first="Jean" last="Mantz">Jean Mantz</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Inserm, U676, Hôpital Robert Debré, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Inserm, U676, Hôpital Robert Debré, Paris</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">Univ Paris Diderot, Sorbonne Paris Cité, UMRS 676, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Univ Paris Diderot, Sorbonne Paris Cité, UMRS 676, Paris</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A3">PremUP, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>PremUP, Paris</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A15">AP HP, Beaujon Hospital, Department of Anesthesia and Critical Care, Clichy, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>AP HP, Beaujon Hospital, Department of Anesthesia and Critical Care, Clichy</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Kavelaars, Annemieke" sort="Kavelaars, Annemieke" uniqKey="Kavelaars A" first="Annemieke" last="Kavelaars">Annemieke Kavelaars</name>
<affiliation wicri:level="1"><nlm:aff id="A6">Laboratory for Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands</nlm:aff>
<country xml:lang="fr">Pays-Bas</country>
<wicri:regionArea>Laboratory for Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A16">Integrative Immunology & Behavior Program, University of Illinois Urbana Champaign, IL, USA</nlm:aff>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Integrative Immunology & Behavior Program, University of Illinois Urbana Champaign, IL</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Gressens, Pierre" sort="Gressens, Pierre" uniqKey="Gressens P" first="Pierre" last="Gressens">Pierre Gressens</name>
<affiliation wicri:level="1"><nlm:aff id="A1">Inserm, U676, Hôpital Robert Debré, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Inserm, U676, Hôpital Robert Debré, Paris</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">Univ Paris Diderot, Sorbonne Paris Cité, UMRS 676, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>Univ Paris Diderot, Sorbonne Paris Cité, UMRS 676, Paris</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A3">PremUP, Paris, France</nlm:aff>
<country xml:lang="fr">France</country>
<wicri:regionArea>PremUP, Paris</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A17">Centre for the Developing Brain, King's College, St Thomas' Campus, London, UK</nlm:aff>
<country xml:lang="fr">Royaume-Uni</country>
<wicri:regionArea>Centre for the Developing Brain, King's College, St Thomas' Campus, London</wicri:regionArea>
</affiliation>
</author>
</analytic>
<series><title level="j">Annals of neurology</title>
<idno type="ISSN">0364-5134</idno>
<idno type="eISSN">1531-8249</idno>
<imprint><date when="2013">2013</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><sec id="S1"><title>Objectives</title>
<p id="P1">The concept of inflammation-induced sensitization is emerging in the field of perinatal brain injury, stroke, Alzheimer disease and multiple sclerosis. However, mechanisms underpinning this process remain unidentified.</p>
</sec>
<sec id="S2"><title>Methods</title>
<p id="P2">We combined <italic>in vivo</italic>
 systemic lipopolysaccharide (LPS) or Interleukin-1β (IL-1β) induced sensitization of neonatal and adult rodent cortical neurons to excitotoxic neurodegeneration with <italic>in vitro</italic>
 IL-1β sensitization of human and rodent neurons to excitotoxic neurodegeneration. Within these inflammation-induced sensitization models we assessed metabotropic glutamatergic receptor (mGluR) signaling and regulation.</p>
</sec>
<sec id="S3"><title>Results</title>
<p id="P3">We demonstrate for the first time that group I mGluRs mediate inflammation-induced sensitization to neuronal excitotoxicity in neonatal and adult neurons across species. Inflammation induced G protein–coupled receptor kinase 2 (GRK2) down-regulation and genetic deletion of <italic>GRK2</italic>
 mimicked the sensitizing effect of inflammation on excitotoxic neurodegeneration. Thus, we identify GRK2 as a potential molecular link between inflammation and mGluR-mediated sensitization.</p>
</sec>
<sec id="S4"><title>Interpretation</title>
<p id="P4">Collectively, our findings indicate that inflammation-induced sensitization is universal across species and ages and that group I mGluRs and GRK2 represent new avenues for neuroprotection in perinatal and adult neurological disorders.</p>
</sec>
</div>
</front>
</TEI>
<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
  <pmc-dir>properties manuscript</pmc-dir>
  <front><journal-meta><journal-id journal-id-type="nlm-journal-id">7707449</journal-id>
<journal-id journal-id-type="pubmed-jr-id">656</journal-id>
<journal-id journal-id-type="nlm-ta">Ann Neurol</journal-id>
<journal-id journal-id-type="iso-abbrev">Ann. Neurol.</journal-id>
<journal-title-group><journal-title>Annals of neurology</journal-title>
</journal-title-group>
<issn pub-type="ppub">0364-5134</issn>
<issn pub-type="epub">1531-8249</issn>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">23494575</article-id>
<article-id pub-id-type="pmc">3837433</article-id>
<article-id pub-id-type="doi">10.1002/ana.23868</article-id>
<article-id pub-id-type="manuscript">NIHMS516317</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>GRK2 and group I mGluR mediate inflammation-induced sensitization to excitotoxic neurodegeneration</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Degos</surname>
<given-names>Vincent</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
<xref ref-type="aff" rid="A3">3</xref>
<xref ref-type="aff" rid="A4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Peineau</surname>
<given-names>Stéphane</given-names>
</name>
<xref rid="FN2" ref-type="author-notes">*</xref>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
<xref ref-type="aff" rid="A3">3</xref>
<xref ref-type="aff" rid="A5">5</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Nijboer</surname>
<given-names>Cora</given-names>
</name>
<xref rid="FN2" ref-type="author-notes">*</xref>
<xref ref-type="aff" rid="A6">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kaindl</surname>
<given-names>Angela M.</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
<xref ref-type="aff" rid="A3">3</xref>
<xref rid="FN3" ref-type="author-notes">§</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Sigaut</surname>
<given-names>Stéphanie</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
<xref ref-type="aff" rid="A3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Favrais</surname>
<given-names>Géraldine</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
<xref ref-type="aff" rid="A3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Plaisant</surname>
<given-names>Frank</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
<xref ref-type="aff" rid="A3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Teissier</surname>
<given-names>Natacha</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
<xref ref-type="aff" rid="A3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Gouadon</surname>
<given-names>Elodie</given-names>
</name>
<xref ref-type="aff" rid="A7">7</xref>
<xref ref-type="aff" rid="A8">8</xref>
<xref ref-type="aff" rid="A9">9</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lombet</surname>
<given-names>Alain</given-names>
</name>
<xref ref-type="aff" rid="A7">7</xref>
<xref ref-type="aff" rid="A9">9</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Saliba</surname>
<given-names>Elie</given-names>
</name>
<xref ref-type="aff" rid="A10">10</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Collingridge</surname>
<given-names>Graham L.</given-names>
</name>
<xref ref-type="aff" rid="A5">5</xref>
<xref ref-type="aff" rid="A11">11</xref>
<xref ref-type="aff" rid="A12">12</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Maze</surname>
<given-names>Mervyn</given-names>
</name>
<xref ref-type="aff" rid="A4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Nicoletti</surname>
<given-names>Ferdinando</given-names>
</name>
<xref ref-type="aff" rid="A13">13</xref>
<xref ref-type="aff" rid="A14">14</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Heijnen</surname>
<given-names>Cobi</given-names>
</name>
<xref ref-type="aff" rid="A6">6</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Mantz</surname>
<given-names>Jean</given-names>
</name>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
<xref ref-type="aff" rid="A3">3</xref>
<xref ref-type="aff" rid="A15">15</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Kavelaars</surname>
<given-names>Annemieke</given-names>
</name>
<xref rid="FN2" ref-type="author-notes">#</xref>
<xref ref-type="aff" rid="A6">6</xref>
<xref ref-type="aff" rid="A16">16</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Gressens</surname>
<given-names>Pierre</given-names>
</name>
<xref rid="FN2" ref-type="author-notes">#</xref>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
<xref ref-type="aff" rid="A3">3</xref>
<xref ref-type="aff" rid="A17">17</xref>
</contrib>
</contrib-group>
<aff id="A1"><label>1</label>
Inserm, U676, Hôpital Robert Debré, Paris, France</aff>
<aff id="A2"><label>2</label>
Univ Paris Diderot, Sorbonne Paris Cité, UMRS 676, Paris, France</aff>
<aff id="A3"><label>3</label>
PremUP, Paris, France</aff>
<aff id="A4"><label>4</label>
Department of Anesthesia and Perioperative Care, University of California, San Francisco, USA</aff>
<aff id="A5"><label>5</label>
MRC Centre for Synaptic Plasticity, School of Physiology and Pharmacology, Medical Sciences Building, Bristol, UK</aff>
<aff id="A6"><label>6</label>
Laboratory for Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands</aff>
<aff id="A7"><label>7</label>
Inserm, UMR 999, Labex LERMIT, Le Plessis-Robinson, France</aff>
<aff id="A8"><label>8</label>
Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France</aff>
<aff id="A9"><label>9</label>
Université Paris-Sud, Faculté de Médecine, Le Kremlin-Bicêtre, France</aff>
<aff id="A10"><label>10</label>
Inserm, U930, Université François Rabelais de Tours, Tours, France</aff>
<aff id="A11"><label>11</label>
Brain Research Centre, Department of Psychiatry, University of British Columbia, Vancouver, Canada</aff>
<aff id="A12"><label>12</label>
Department of Brain and Cognitive Sciences, Seoul National University, Seoul, Korea</aff>
<aff id="A13"><label>13</label>
Dept. of Physiology and Pharmacology, University of Rome Sapienza, Italy</aff>
<aff id="A14"><label>14</label>
IRCCS Neuromed, Pozzilli (IS), Italy</aff>
<aff id="A15"><label>15</label>
AP HP, Beaujon Hospital, Department of Anesthesia and Critical Care, Clichy, France</aff>
<aff id="A16"><label>16</label>
Integrative Immunology & Behavior Program, University of Illinois Urbana Champaign, IL, USA</aff>
<aff id="A17"><label>17</label>
Centre for the Developing Brain, King's College, St Thomas' Campus, London, UK</aff>
<author-notes><corresp id="FN1">Corresponding author: Dr Pierre Gressens, Inserm U676, Hôpital Robert Debré, 48 blvd Serurier, F-75019 Paris, France. Phone: +33 1 40 03 19 76; Fax: +33 1 40 03 19 95; <email>pierre.gressens@inserm.fr</email>
</corresp>
<fn id="FN2" fn-type="equal"><label>*#</label>
<p>These authors have equally contributed to the manuscript</p>
</fn>
<fn id="FN3" fn-type="present-address"><label>§</label>
<p>Current addresses: Department of Pediatric Neurology and Institute of Cell and Neurobiology, Charité University Medicine Berlin, Universitätsmedizin, 10117 Berlin, Germany</p>
</fn>
</author-notes>
<pub-date pub-type="nihms-submitted"><day>27</day>
<month>9</month>
<year>2013</year>
</pub-date>
<pub-date pub-type="epub"><day>14</day>
<month>3</month>
<year>2013</year>
</pub-date>
<pub-date pub-type="ppub"><month>5</month>
<year>2013</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>01</day>
<month>5</month>
<year>2014</year>
</pub-date>
<volume>73</volume>
<issue>5</issue>
<elocation-id>10.1002/ana.23868</elocation-id>
<abstract><sec id="S1"><title>Objectives</title>
<p id="P1">The concept of inflammation-induced sensitization is emerging in the field of perinatal brain injury, stroke, Alzheimer disease and multiple sclerosis. However, mechanisms underpinning this process remain unidentified.</p>
</sec>
<sec id="S2"><title>Methods</title>
<p id="P2">We combined <italic>in vivo</italic>
 systemic lipopolysaccharide (LPS) or Interleukin-1β (IL-1β) induced sensitization of neonatal and adult rodent cortical neurons to excitotoxic neurodegeneration with <italic>in vitro</italic>
 IL-1β sensitization of human and rodent neurons to excitotoxic neurodegeneration. Within these inflammation-induced sensitization models we assessed metabotropic glutamatergic receptor (mGluR) signaling and regulation.</p>
</sec>
<sec id="S3"><title>Results</title>
<p id="P3">We demonstrate for the first time that group I mGluRs mediate inflammation-induced sensitization to neuronal excitotoxicity in neonatal and adult neurons across species. Inflammation induced G protein–coupled receptor kinase 2 (GRK2) down-regulation and genetic deletion of <italic>GRK2</italic>
 mimicked the sensitizing effect of inflammation on excitotoxic neurodegeneration. Thus, we identify GRK2 as a potential molecular link between inflammation and mGluR-mediated sensitization.</p>
</sec>
<sec id="S4"><title>Interpretation</title>
<p id="P4">Collectively, our findings indicate that inflammation-induced sensitization is universal across species and ages and that group I mGluRs and GRK2 represent new avenues for neuroprotection in perinatal and adult neurological disorders.</p>
</sec>
</abstract>
<funding-group><award-group><funding-source country="United States">National Institute of Neurological Disorders and Stroke : NINDS</funding-source>
<award-id>R01 NS074999 || NS</award-id>
</award-group>
<award-group><funding-source country="United States">National Institute of Neurological Disorders and Stroke : NINDS</funding-source>
<award-id>R01 NS073939 || NS</award-id>
</award-group>
</funding-group>
</article-meta>
</front>
</pmc>
</record>

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GRK2 and group I mGluR mediate inflammation-induced sensitization to excitotoxic neurodegeneration

GRK2 and group I mGluR mediate inflammation-induced sensitization to excitotoxic neurodegeneration

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