title: PAR1-activated astrocytes in the nucleus of the solitary tract stimulate adjacent neurons via NMDA receptors.
abstract: Severe autonomic dysfunction, including the loss of control of the cardiovascular, respiratory, and gastrointestinal systems, is a common comorbidity of stroke and other bleeding head injuries. Previous studies suggest that this collapse of autonomic control may be caused by thrombin acting on astrocytic protease-activated receptors (PAR1) in the hindbrain. Using calcium imaging and electrophysiological techniques, we evaluated the mechanisms by which astrocytic PAR1s modulate the activity of presynaptic vagal afferent terminals and postsynaptic neurons in the rat nucleus of the solitary tract (NST). Our calcium-imaging data show that astrocytic and neuronal calcium levels increase after brain slices are treated with the PAR1 agonist SFLLRN-NH2. This increase in activity is blocked by pretreating the slices with the glial metabolic blocker fluorocitrate. In addition, PAR1-activated astrocytes communicate directly with NST neurons by releasing glutamate. Calcium responses to SFLLRN-NH2 in the astrocytes and neurons significantly increase after bath application of the excitatory amino acid transporter blocker DL-threo-β-benzyloxyaspartic acid (TBOA) and significantly decrease after bath application of the NMDA receptor antagonist DL-2-amino-5-phosphonopentanoic acid (DL-AP5). Furthermore, astrocytic glutamate activates neuronal GluN2B-containing NMDA receptors. Voltage-clamp recordings of miniature EPSCs (mEPSCs) from NST neurons show that astrocytes control presynaptic vagal afferent excitability directly under resting and activated conditions. Fluorocitrate significantly decreases mEPSC frequency and SFLLRN-NH2 significantly increases mEPSC frequency. These data show that astrocytes act within a tripartite synapse in the NST, controlling the excitability of both postsynaptic NST neurons and presynaptic vagal afferent terminals.
authors.affiliation: Laboratory of Autonomic Neuroscience, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana 70808.
authors.forename: Katie M
authors.initials: KM
authors.lastname: Vance
authors.affiliation: Laboratory of Autonomic Neuroscience, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana 70808.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Rogers
authors.affiliation: Laboratory of Autonomic Neuroscience, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana 70808 gerlinda.hermann@pbrc.edu.
authors.forename: Gerlinda E
authors.identifier: http://orcid.org/0000-0003-0405-2820
authors.initials: GE
authors.lastname: Hermann
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000818:Animals; D001224:Aspartic Acid / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002951:Citrates / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists; D019706:Excitatory Postsynaptic Potentials; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism; D008297:Male; D055369:Miniature Postsynaptic Potentials; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D044463:Receptor, PAR-1 / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017552:Solitary Nucleus / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D013569:Synapses / Q000378:metabolism / Q000502:physiology; D014630:Vagus Nerve / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D010975:Platelet Aggregation Inhibitors
chemical_list: D002951:Citrates; D018691:Excitatory Amino Acid Antagonists; C121001:NR2B NMDA receptor; D010446:Peptide Fragments; D044463:Receptor, PAR-1; D016194:Receptors, N-Methyl-D-Aspartate; C120673:benzyloxyaspartate; C082835:thrombin receptor peptide (42-47); D001224:Aspartic Acid; C007744:fluorocitrate; D018698:Glutamic Acid; D015763:2-Amino-5-phosphonovalerate; D002118:Calcium; D010975:Platelet Aggregation Inhibitors
keywords: GluN2B; calcium imaging; electrophysiology; gliotransmitter; mEPSC; tripartite synapse