title: PAR1 activation induces rapid changes in glutamate uptake and astrocyte morphology.
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.
authors.affiliation: SUNY Albany, Dept. Biology, 1400 Washington Avenue, Albany NY 12222, USA.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Sweeney
authors.affiliation: SUNY Albany, Dept. Biology, 1400 Washington Avenue, Albany NY 12222, USA.
authors.forename: Kelsey E
authors.initials: KE
authors.lastname: Fleming
authors.affiliation: SUNY Albany, Dept. Biology, 1400 Washington Avenue, Albany NY 12222, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: McCauley
authors.affiliation: SUNY Albany, Dept. Biology, 1400 Washington Avenue, Albany NY 12222, USA.|SUNY Oneonta, Dept. Computer Science, 108 Ravine Parkway, Oneonta NY 13820, USA.
authors.forename: Marvin F
authors.initials: MF
authors.lastname: Rodriguez
authors.affiliation: SUNY Albany, Dept. Biology, 1400 Washington Avenue, Albany NY 12222, USA.
authors.forename: Elliot T
authors.initials: ET
authors.lastname: Martin
authors.affiliation: National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, 9000 Rockville Pike, Bethesda MD 20852, USA.
authors.forename: Alioscka A
authors.initials: AA
authors.lastname: Sousa
authors.affiliation: National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, 9000 Rockville Pike, Bethesda MD 20852, USA.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Leapman
authors.affiliation: SUNY Albany, Dept. Biology, 1400 Washington Avenue, Albany NY 12222, USA.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Scimemi
mesh_terms: D000465:Algorithms; D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000648:ultrastructure; D001692:Biological Transport; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism / Q000648:ultrastructure; D021621:Imaging, Three-Dimensional; D017774:Long-Term Potentiation; D008297:Male; D051379:Mice; D008954:Models, Biological; D009010:Monte Carlo Method; D009474:Neurons / Q000378:metabolism; D044463:Receptor, PAR-1 / Q000819:agonists*; D018091:Receptors, AMPA / Q000378:metabolism; D055366:Synaptic Potentials; D009435:Synaptic Transmission
chemical_list: D044463:Receptor, PAR-1; D018091:Receptors, AMPA; D018698:Glutamic Acid