PAR1 activation induces rapid changes in glutamate uptake and astrocyte morphology
The G-protein coupled, protease-activated receptor 1 (PAR1) is a membrane protein expressed in astrocytes. Fine astrocytic processes are in tight contact with neurons and blood vessels and shape excitatory synaptic transmission due to their abundant expression of glutamate transporters. PAR1 is prot...
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description | The G-protein coupled, protease-activated receptor 1 (PAR1) is a membrane protein expressed in astrocytes. Fine astrocytic processes are in tight contact with neurons and blood vessels and shape excitatory synaptic transmission due to their abundant expression of glutamate transporters. PAR1 is proteolytically-activated by bloodstream serine proteases also involved in the formation of blood clots. PAR1 activation has been suggested to play a key role in pathological states like thrombosis, hemostasis and inflammation. What remains unclear is whether PAR1 activation also regulates glutamate uptake in astrocytes and how this shapes excitatory synaptic transmission among neurons. Here we show that, in the mouse hippocampus, PAR1 activation induces a rapid structural re-organization of the neuropil surrounding glutamatergic synapses, which is associated with faster clearance of synaptically-released glutamate from the extracellular space. This effect can be recapitulated using realistic 3D Monte Carlo reaction-diffusion simulations, based on axial scanning transmission electron microscopy (STEM) tomography reconstructions of excitatory synapses. The faster glutamate clearance induced by PAR1 activation leads to short- and long-term changes in excitatory synaptic transmission. Together, these findings identify PAR1 as an important regulator of glutamatergic signaling in the hippocampus and a possible target molecule to limit brain damage during hemorrhagic stroke. |
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Fine astrocytic processes are in tight contact with neurons and blood vessels and shape excitatory synaptic transmission due to their abundant expression of glutamate transporters. PAR1 is proteolytically-activated by bloodstream serine proteases also involved in the formation of blood clots. PAR1 activation has been suggested to play a key role in pathological states like thrombosis, hemostasis and inflammation. What remains unclear is whether PAR1 activation also regulates glutamate uptake in astrocytes and how this shapes excitatory synaptic transmission among neurons. Here we show that, in the mouse hippocampus, PAR1 activation induces a rapid structural re-organization of the neuropil surrounding glutamatergic synapses, which is associated with faster clearance of synaptically-released glutamate from the extracellular space. This effect can be recapitulated using realistic 3D Monte Carlo reaction-diffusion simulations, based on axial scanning transmission electron microscopy (STEM) tomography reconstructions of excitatory synapses. The faster glutamate clearance induced by PAR1 activation leads to short- and long-term changes in excitatory synaptic transmission. Together, these findings identify PAR1 as an important regulator of glutamatergic signaling in the hippocampus and a possible target molecule to limit brain damage during hemorrhagic stroke.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/srep43606</identifier><identifier>PMID: 28256580</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>14/28 ; 14/34 ; 14/5 ; 14/63 ; 14/69 ; 631/378/116/2392 ; 631/378/87 ; 64/60 ; 9/74 ; Algorithms ; Animals ; Astrocytes ; Astrocytes - metabolism ; Astrocytes - ultrastructure ; Biological Transport ; Blood coagulation ; Blood vessels ; Brain injury ; Electron microscopy ; Female ; Glutamatergic transmission ; Glutamic Acid - metabolism ; Hemorrhage ; Hemostasis ; Hippocampus ; Hippocampus - metabolism ; Hippocampus - ultrastructure ; Humanities and Social Sciences ; Imaging, Three-Dimensional ; Long-Term Potentiation ; Male ; Membrane proteins ; Mice ; Models, Biological ; Monte Carlo Method ; multidisciplinary ; Neurons - metabolism ; Neuropil ; Proteinase-activated receptor 1 ; Receptor, PAR-1 - agonists ; Receptors, AMPA - metabolism ; Rodents ; Science ; Serine ; Stroke ; Synapses ; Synaptic Potentials ; Synaptic Transmission ; Thromboembolism ; Thrombosis ; Transmission electron microscopy</subject><ispartof>Scientific reports, 2017-03, Vol.7 (1), p.43606-43606, Article 43606</ispartof><rights>The Author(s) 2017</rights><rights>Copyright Nature Publishing Group Mar 2017</rights><rights>Copyright © 2017, The Author(s) 2017 The Author(s)</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c438t-edbe085c9e3e7ab5889139048e8450d036a15c606cfb9a1c6a8ecc7dc76144733</citedby><cites>FETCH-LOGICAL-c438t-edbe085c9e3e7ab5889139048e8450d036a15c606cfb9a1c6a8ecc7dc76144733</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5335386/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5335386/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27923,27924,41119,42188,51575,53790,53792</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28256580$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sweeney, Amanda M.</creatorcontrib><creatorcontrib>Fleming, Kelsey E.</creatorcontrib><creatorcontrib>McCauley, John P.</creatorcontrib><creatorcontrib>Rodriguez, Marvin F.</creatorcontrib><creatorcontrib>Martin, Elliot T.</creatorcontrib><creatorcontrib>Sousa, Alioscka A.</creatorcontrib><creatorcontrib>Leapman, Richard D.</creatorcontrib><creatorcontrib>Scimemi, Annalisa</creatorcontrib><title>PAR1 activation induces rapid changes in glutamate uptake and astrocyte morphology</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>The G-protein coupled, protease-activated receptor 1 (PAR1) is a membrane protein expressed in astrocytes. Fine astrocytic processes are in tight contact with neurons and blood vessels and shape excitatory synaptic transmission due to their abundant expression of glutamate transporters. PAR1 is proteolytically-activated by bloodstream serine proteases also involved in the formation of blood clots. PAR1 activation has been suggested to play a key role in pathological states like thrombosis, hemostasis and inflammation. What remains unclear is whether PAR1 activation also regulates glutamate uptake in astrocytes and how this shapes excitatory synaptic transmission among neurons. Here we show that, in the mouse hippocampus, PAR1 activation induces a rapid structural re-organization of the neuropil surrounding glutamatergic synapses, which is associated with faster clearance of synaptically-released glutamate from the extracellular space. This effect can be recapitulated using realistic 3D Monte Carlo reaction-diffusion simulations, based on axial scanning transmission electron microscopy (STEM) tomography reconstructions of excitatory synapses. The faster glutamate clearance induced by PAR1 activation leads to short- and long-term changes in excitatory synaptic transmission. Together, these findings identify PAR1 as an important regulator of glutamatergic signaling in the hippocampus and a possible target molecule to limit brain damage during hemorrhagic stroke.</description><subject>14/28</subject><subject>14/34</subject><subject>14/5</subject><subject>14/63</subject><subject>14/69</subject><subject>631/378/116/2392</subject><subject>631/378/87</subject><subject>64/60</subject><subject>9/74</subject><subject>Algorithms</subject><subject>Animals</subject><subject>Astrocytes</subject><subject>Astrocytes - metabolism</subject><subject>Astrocytes - ultrastructure</subject><subject>Biological Transport</subject><subject>Blood coagulation</subject><subject>Blood vessels</subject><subject>Brain injury</subject><subject>Electron microscopy</subject><subject>Female</subject><subject>Glutamatergic transmission</subject><subject>Glutamic Acid - metabolism</subject><subject>Hemorrhage</subject><subject>Hemostasis</subject><subject>Hippocampus</subject><subject>Hippocampus - metabolism</subject><subject>Hippocampus - ultrastructure</subject><subject>Humanities and Social Sciences</subject><subject>Imaging, Three-Dimensional</subject><subject>Long-Term Potentiation</subject><subject>Male</subject><subject>Membrane proteins</subject><subject>Mice</subject><subject>Models, Biological</subject><subject>Monte Carlo Method</subject><subject>multidisciplinary</subject><subject>Neurons - metabolism</subject><subject>Neuropil</subject><subject>Proteinase-activated receptor 1</subject><subject>Receptor, PAR-1 - agonists</subject><subject>Receptors, AMPA - metabolism</subject><subject>Rodents</subject><subject>Science</subject><subject>Serine</subject><subject>Stroke</subject><subject>Synapses</subject><subject>Synaptic Potentials</subject><subject>Synaptic Transmission</subject><subject>Thromboembolism</subject><subject>Thrombosis</subject><subject>Transmission electron microscopy</subject><issn>2045-2322</issn><issn>2045-2322</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNplkV1LBCEUhiWKiuqiPxAD3VSwpaPO6E0Q0RcERdS1nHXcXWtGJ3WC_fcZW8tW3hz1PLzn40Von-BTgqk4i8H0jFa4WkPbJWZ8VNKyXF-5b6G9GF9xPryUjMhNtFWKkldc4G309HjxRArQyX5Ast4V1jWDNrEI0Num0DNw0_yyrpi2Q4IOkimGPsGbKcA1BcQUvJ7nz86HfuZbP53voo0JtNHsfccd9HJ99Xx5O7p_uLm7vLgfaUZFGplmbLDgWhpqahhzISShEjNhBOO4wbQCwnWeS0_GEoiuQBit60bXFWGspnQHnS90-2HcmUYblwK0qg-2gzBXHqz6nXF2pqb-Q3FKORVVFjj6Fgj-fTAxqc5GbdoWnPFDVETUjOXVSpbRwz_oqx-Cy-MpIjGlFZWEZ-p4QengY_ZlsmyGYPVlllqaldmD1e6X5I81GThZADGnsglhpeQ_tU_7lJ6q</recordid><startdate>20170303</startdate><enddate>20170303</enddate><creator>Sweeney, Amanda M.</creator><creator>Fleming, Kelsey E.</creator><creator>McCauley, John P.</creator><creator>Rodriguez, Marvin F.</creator><creator>Martin, Elliot T.</creator><creator>Sousa, Alioscka A.</creator><creator>Leapman, Richard D.</creator><creator>Scimemi, Annalisa</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><scope>C6C</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>3V.</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>88I</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2P</scope><scope>M7P</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20170303</creationdate><title>PAR1 activation induces rapid changes in glutamate uptake and astrocyte morphology</title><author>Sweeney, Amanda M. ; Fleming, Kelsey E. ; McCauley, John P. ; Rodriguez, Marvin F. ; Martin, Elliot T. ; Sousa, Alioscka A. ; Leapman, Richard D. ; Scimemi, Annalisa</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c438t-edbe085c9e3e7ab5889139048e8450d036a15c606cfb9a1c6a8ecc7dc76144733</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>14/28</topic><topic>14/34</topic><topic>14/5</topic><topic>14/63</topic><topic>14/69</topic><topic>631/378/116/2392</topic><topic>631/378/87</topic><topic>64/60</topic><topic>9/74</topic><topic>Algorithms</topic><topic>Animals</topic><topic>Astrocytes</topic><topic>Astrocytes - metabolism</topic><topic>Astrocytes - ultrastructure</topic><topic>Biological Transport</topic><topic>Blood coagulation</topic><topic>Blood vessels</topic><topic>Brain injury</topic><topic>Electron microscopy</topic><topic>Female</topic><topic>Glutamatergic transmission</topic><topic>Glutamic Acid - metabolism</topic><topic>Hemorrhage</topic><topic>Hemostasis</topic><topic>Hippocampus</topic><topic>Hippocampus - metabolism</topic><topic>Hippocampus - ultrastructure</topic><topic>Humanities and Social Sciences</topic><topic>Imaging, Three-Dimensional</topic><topic>Long-Term Potentiation</topic><topic>Male</topic><topic>Membrane proteins</topic><topic>Mice</topic><topic>Models, Biological</topic><topic>Monte Carlo Method</topic><topic>multidisciplinary</topic><topic>Neurons - metabolism</topic><topic>Neuropil</topic><topic>Proteinase-activated receptor 1</topic><topic>Receptor, PAR-1 - agonists</topic><topic>Receptors, AMPA - metabolism</topic><topic>Rodents</topic><topic>Science</topic><topic>Serine</topic><topic>Stroke</topic><topic>Synapses</topic><topic>Synaptic Potentials</topic><topic>Synaptic Transmission</topic><topic>Thromboembolism</topic><topic>Thrombosis</topic><topic>Transmission electron microscopy</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sweeney, Amanda M.</creatorcontrib><creatorcontrib>Fleming, Kelsey E.</creatorcontrib><creatorcontrib>McCauley, John P.</creatorcontrib><creatorcontrib>Rodriguez, Marvin F.</creatorcontrib><creatorcontrib>Martin, Elliot T.</creatorcontrib><creatorcontrib>Sousa, Alioscka A.</creatorcontrib><creatorcontrib>Leapman, Richard D.</creatorcontrib><creatorcontrib>Scimemi, Annalisa</creatorcontrib><collection>Springer Nature OA/Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Science Database (Alumni Edition)</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Science Database</collection><collection>Biological Science Database</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sweeney, Amanda M.</au><au>Fleming, Kelsey E.</au><au>McCauley, John P.</au><au>Rodriguez, Marvin F.</au><au>Martin, Elliot T.</au><au>Sousa, Alioscka A.</au><au>Leapman, Richard D.</au><au>Scimemi, Annalisa</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>PAR1 activation induces rapid changes in glutamate uptake and astrocyte morphology</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2017-03-03</date><risdate>2017</risdate><volume>7</volume><issue>1</issue><spage>43606</spage><epage>43606</epage><pages>43606-43606</pages><artnum>43606</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>The G-protein coupled, protease-activated receptor 1 (PAR1) is a membrane protein expressed in astrocytes. Fine astrocytic processes are in tight contact with neurons and blood vessels and shape excitatory synaptic transmission due to their abundant expression of glutamate transporters. PAR1 is proteolytically-activated by bloodstream serine proteases also involved in the formation of blood clots. PAR1 activation has been suggested to play a key role in pathological states like thrombosis, hemostasis and inflammation. What remains unclear is whether PAR1 activation also regulates glutamate uptake in astrocytes and how this shapes excitatory synaptic transmission among neurons. Here we show that, in the mouse hippocampus, PAR1 activation induces a rapid structural re-organization of the neuropil surrounding glutamatergic synapses, which is associated with faster clearance of synaptically-released glutamate from the extracellular space. This effect can be recapitulated using realistic 3D Monte Carlo reaction-diffusion simulations, based on axial scanning transmission electron microscopy (STEM) tomography reconstructions of excitatory synapses. The faster glutamate clearance induced by PAR1 activation leads to short- and long-term changes in excitatory synaptic transmission. Together, these findings identify PAR1 as an important regulator of glutamatergic signaling in the hippocampus and a possible target molecule to limit brain damage during hemorrhagic stroke.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>28256580</pmid><doi>10.1038/srep43606</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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subjects | 14/28 14/34 14/5 14/63 14/69 631/378/116/2392 631/378/87 64/60 9/74 Algorithms Animals Astrocytes Astrocytes - metabolism Astrocytes - ultrastructure Biological Transport Blood coagulation Blood vessels Brain injury Electron microscopy Female Glutamatergic transmission Glutamic Acid - metabolism Hemorrhage Hemostasis Hippocampus Hippocampus - metabolism Hippocampus - ultrastructure Humanities and Social Sciences Imaging, Three-Dimensional Long-Term Potentiation Male Membrane proteins Mice Models, Biological Monte Carlo Method multidisciplinary Neurons - metabolism Neuropil Proteinase-activated receptor 1 Receptor, PAR-1 - agonists Receptors, AMPA - metabolism Rodents Science Serine Stroke Synapses Synaptic Potentials Synaptic Transmission Thromboembolism Thrombosis Transmission electron microscopy |
title | PAR1 activation induces rapid changes in glutamate uptake and astrocyte morphology |
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