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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Veröffentlicht in:Scientific reports 2017-03, Vol.7 (1), p.43606-43606, Article 43606
Hauptverfasser: Sweeney, Amanda M., Fleming, Kelsey E., McCauley, John P., Rodriguez, Marvin F., Martin, Elliot T., Sousa, Alioscka A., Leapman, Richard D., Scimemi, Annalisa
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container_title Scientific reports
container_volume 7
creator Sweeney, Amanda M.
Fleming, Kelsey E.
McCauley, John P.
Rodriguez, Marvin F.
Martin, Elliot T.
Sousa, Alioscka A.
Leapman, Richard D.
Scimemi, Annalisa
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.
doi_str_mv 10.1038/srep43606
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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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