Glutamate Receptor Expression in Multiple Sclerosis Lesions
Blockade of receptors for the excitatory neurotransmitter glutamate ameliorates neurological clinical signs in models of the CNS inflammatory demyelinating disease multiple sclerosis (MS). To investigate whether glutamate excitoxicity may play a role in MS pathogenesis, the cellular localization of...
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Veröffentlicht in: | Brain pathology (Zurich, Switzerland) Switzerland), 2008-01, Vol.18 (1), p.52-61 |
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description | Blockade of receptors for the excitatory neurotransmitter glutamate ameliorates neurological clinical signs in models of the CNS inflammatory demyelinating disease multiple sclerosis (MS). To investigate whether glutamate excitoxicity may play a role in MS pathogenesis, the cellular localization of glutamate and its receptors, transporters and enzymes was examined. Expression of glutamate receptor (GluR) 1, a Ca++‐permeable ionotropic AMPA receptor subunit, was up‐regulated on oligodendrocytes in active MS lesion borders, but Ca++‐impermeable AMPA GluR2 subunit levels were not increased. Reactive astrocytes in active plaques expressed AMPA GluR3 and metabotropic mGluR1, 2/3 and 5 receptors and the GLT‐1 transporter, and a subpopulation was immunostained with glutamate antibodies. Activated microglia and macrophages were immunopositive for GluR2, GluR4 and NMDA receptor subunit 1. Kainate receptor GluR5–7 immunostaining showed endothelial cells and dystrophic axons. Astrocyte and macrophage populations expressed glutamate metabolizing enzymes and unexpectedly the EAAC1 transporter, which may play a role in glutamate uptake in lesions. Thus, reactive astrocytes in MS white matter lesions are equipped for a protective role in sequestering and metabolizing extracellular glutamate. However, they may be unable to maintain glutamate at levels low enough to protect oligodendrocytes rendered vulnerable to excitotoxic damage because of GluR1 up‐regulation. |
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To investigate whether glutamate excitoxicity may play a role in MS pathogenesis, the cellular localization of glutamate and its receptors, transporters and enzymes was examined. Expression of glutamate receptor (GluR) 1, a Ca++‐permeable ionotropic AMPA receptor subunit, was up‐regulated on oligodendrocytes in active MS lesion borders, but Ca++‐impermeable AMPA GluR2 subunit levels were not increased. Reactive astrocytes in active plaques expressed AMPA GluR3 and metabotropic mGluR1, 2/3 and 5 receptors and the GLT‐1 transporter, and a subpopulation was immunostained with glutamate antibodies. Activated microglia and macrophages were immunopositive for GluR2, GluR4 and NMDA receptor subunit 1. Kainate receptor GluR5–7 immunostaining showed endothelial cells and dystrophic axons. Astrocyte and macrophage populations expressed glutamate metabolizing enzymes and unexpectedly the EAAC1 transporter, which may play a role in glutamate uptake in lesions. Thus, reactive astrocytes in MS white matter lesions are equipped for a protective role in sequestering and metabolizing extracellular glutamate. 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To investigate whether glutamate excitoxicity may play a role in MS pathogenesis, the cellular localization of glutamate and its receptors, transporters and enzymes was examined. Expression of glutamate receptor (GluR) 1, a Ca++‐permeable ionotropic AMPA receptor subunit, was up‐regulated on oligodendrocytes in active MS lesion borders, but Ca++‐impermeable AMPA GluR2 subunit levels were not increased. Reactive astrocytes in active plaques expressed AMPA GluR3 and metabotropic mGluR1, 2/3 and 5 receptors and the GLT‐1 transporter, and a subpopulation was immunostained with glutamate antibodies. Activated microglia and macrophages were immunopositive for GluR2, GluR4 and NMDA receptor subunit 1. Kainate receptor GluR5–7 immunostaining showed endothelial cells and dystrophic axons. Astrocyte and macrophage populations expressed glutamate metabolizing enzymes and unexpectedly the EAAC1 transporter, which may play a role in glutamate uptake in lesions. Thus, reactive astrocytes in MS white matter lesions are equipped for a protective role in sequestering and metabolizing extracellular glutamate. However, they may be unable to maintain glutamate at levels low enough to protect oligodendrocytes rendered vulnerable to excitotoxic damage because of GluR1 up‐regulation.</description><subject>Adult</subject><subject>Aged</subject><subject>Aged, 80 and over</subject><subject>Astrocytes - metabolism</subject><subject>Astrocytes - pathology</subject><subject>Central Nervous System - metabolism</subject><subject>Central Nervous System - pathology</subject><subject>Central Nervous System - physiopathology</subject><subject>Excitatory Amino Acid Transporter 3 - metabolism</subject><subject>Female</subject><subject>Gliosis - metabolism</subject><subject>Gliosis - pathology</subject><subject>Gliosis - physiopathology</subject><subject>Glutamic Acid - metabolism</subject><subject>Humans</subject><subject>Macrophages - metabolism</subject><subject>Macrophages - pathology</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Multiple Sclerosis - metabolism</subject><subject>Multiple Sclerosis - pathology</subject><subject>Multiple Sclerosis - physiopathology</subject><subject>Nerve Fibers, Myelinated - metabolism</subject><subject>Nerve Fibers, Myelinated - pathology</subject><subject>Neuroglia - metabolism</subject><subject>Neuroglia - pathology</subject><subject>Neurotoxins - metabolism</subject><subject>Oligodendroglia - metabolism</subject><subject>Oligodendroglia - pathology</subject><subject>Protein Subunits - metabolism</subject><subject>Receptors, AMPA - metabolism</subject><subject>Receptors, Kainic Acid - metabolism</subject><subject>Vesicular Glutamate Transport Proteins - metabolism</subject><issn>1015-6305</issn><issn>1750-3639</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkFtLwzAUx4MoOi9fQfoFWpNmaRIUYY45xanD6-MhSVPN7NbSdLp9e1snU9_Mywn8L-fwQyggOCLNO5pEhDMc0oTKKMaYRxgTTKLFBuqshc3mjwkLE4rZDtr1ftKYZCLZNtohXMZdKXAHHQ_zea2mqrbBnTW2rIsqGCzKynrvilngZsH1PK9dmdvg3uS2Krzzwci2ot9HW5nKvT34nnvo8Xzw0L8IR7fDy35vFJpmNwm1NiwVQiudck7iRMlMpdrEMdPaSkwFVUQoJlPFWDdlJksF5VJlXW00Ud2E7qHTVW8511ObGjurK5VDWbmpqpZQKAd_lZl7hZfiHQSWLMGkKRCrAtPc7yubrbMEQwsUJtByg5YbtEDhCygsmujh790_wW-CjeFkZfhwuV3-uxjOxj3ydVq4ijtf28U6rqo3SDjlDJ5vhoDZEx-LKwk39BO0aZWF</recordid><startdate>200801</startdate><enddate>200801</enddate><creator>Newcombe, Jia</creator><creator>Uddin, Alim</creator><creator>Dove, Rosamund</creator><creator>Patel, Bela</creator><creator>Turski, Lechoslaw</creator><creator>Nishizawa, Yukio</creator><creator>Smith, Terence</creator><general>Blackwell Publishing Ltd</general><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>200801</creationdate><title>Glutamate Receptor Expression in Multiple Sclerosis Lesions</title><author>Newcombe, Jia ; Uddin, Alim ; Dove, Rosamund ; Patel, Bela ; Turski, Lechoslaw ; Nishizawa, Yukio ; Smith, Terence</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c6301-bbc5d88babd77126a9fadbc225bbe90383a18a59da554d5cfd8379af4bcb1a463</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Aged, 80 and over</topic><topic>Astrocytes - metabolism</topic><topic>Astrocytes - pathology</topic><topic>Central Nervous System - metabolism</topic><topic>Central Nervous System - pathology</topic><topic>Central Nervous System - physiopathology</topic><topic>Excitatory Amino Acid Transporter 3 - metabolism</topic><topic>Female</topic><topic>Gliosis - metabolism</topic><topic>Gliosis - pathology</topic><topic>Gliosis - physiopathology</topic><topic>Glutamic Acid - metabolism</topic><topic>Humans</topic><topic>Macrophages - metabolism</topic><topic>Macrophages - pathology</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Multiple Sclerosis - metabolism</topic><topic>Multiple Sclerosis - pathology</topic><topic>Multiple Sclerosis - physiopathology</topic><topic>Nerve Fibers, Myelinated - metabolism</topic><topic>Nerve Fibers, Myelinated - pathology</topic><topic>Neuroglia - metabolism</topic><topic>Neuroglia - pathology</topic><topic>Neurotoxins - metabolism</topic><topic>Oligodendroglia - metabolism</topic><topic>Oligodendroglia - pathology</topic><topic>Protein Subunits - metabolism</topic><topic>Receptors, AMPA - metabolism</topic><topic>Receptors, Kainic Acid - metabolism</topic><topic>Vesicular Glutamate Transport Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Newcombe, Jia</creatorcontrib><creatorcontrib>Uddin, Alim</creatorcontrib><creatorcontrib>Dove, Rosamund</creatorcontrib><creatorcontrib>Patel, Bela</creatorcontrib><creatorcontrib>Turski, Lechoslaw</creatorcontrib><creatorcontrib>Nishizawa, Yukio</creatorcontrib><creatorcontrib>Smith, Terence</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Brain pathology (Zurich, Switzerland)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Newcombe, Jia</au><au>Uddin, Alim</au><au>Dove, Rosamund</au><au>Patel, Bela</au><au>Turski, Lechoslaw</au><au>Nishizawa, Yukio</au><au>Smith, Terence</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Glutamate Receptor Expression in Multiple Sclerosis Lesions</atitle><jtitle>Brain pathology (Zurich, Switzerland)</jtitle><addtitle>Brain Pathol</addtitle><date>2008-01</date><risdate>2008</risdate><volume>18</volume><issue>1</issue><spage>52</spage><epage>61</epage><pages>52-61</pages><issn>1015-6305</issn><eissn>1750-3639</eissn><abstract>Blockade of receptors for the excitatory neurotransmitter glutamate ameliorates neurological clinical signs in models of the CNS inflammatory demyelinating disease multiple sclerosis (MS). To investigate whether glutamate excitoxicity may play a role in MS pathogenesis, the cellular localization of glutamate and its receptors, transporters and enzymes was examined. Expression of glutamate receptor (GluR) 1, a Ca++‐permeable ionotropic AMPA receptor subunit, was up‐regulated on oligodendrocytes in active MS lesion borders, but Ca++‐impermeable AMPA GluR2 subunit levels were not increased. Reactive astrocytes in active plaques expressed AMPA GluR3 and metabotropic mGluR1, 2/3 and 5 receptors and the GLT‐1 transporter, and a subpopulation was immunostained with glutamate antibodies. Activated microglia and macrophages were immunopositive for GluR2, GluR4 and NMDA receptor subunit 1. Kainate receptor GluR5–7 immunostaining showed endothelial cells and dystrophic axons. Astrocyte and macrophage populations expressed glutamate metabolizing enzymes and unexpectedly the EAAC1 transporter, which may play a role in glutamate uptake in lesions. 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subjects | Adult Aged Aged, 80 and over Astrocytes - metabolism Astrocytes - pathology Central Nervous System - metabolism Central Nervous System - pathology Central Nervous System - physiopathology Excitatory Amino Acid Transporter 3 - metabolism Female Gliosis - metabolism Gliosis - pathology Gliosis - physiopathology Glutamic Acid - metabolism Humans Macrophages - metabolism Macrophages - pathology Male Middle Aged Multiple Sclerosis - metabolism Multiple Sclerosis - pathology Multiple Sclerosis - physiopathology Nerve Fibers, Myelinated - metabolism Nerve Fibers, Myelinated - pathology Neuroglia - metabolism Neuroglia - pathology Neurotoxins - metabolism Oligodendroglia - metabolism Oligodendroglia - pathology Protein Subunits - metabolism Receptors, AMPA - metabolism Receptors, Kainic Acid - metabolism Vesicular Glutamate Transport Proteins - metabolism |
title | Glutamate Receptor Expression in Multiple Sclerosis Lesions |
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