title: Dual modulation of synaptic transmission in the nucleus tractus solitarius by prostaglandin E2 synthesized downstream of IL-1beta.
abstract: The activation of the innate immune system induces the production of blood-borne proinflammatory cytokines like interleukin-1beta (IL-1beta), which in turn triggers brain-mediated adaptative responses referred to as sickness behaviour. These responses involve the modulation of neural networks in key regions of the brain. The nucleus tractus solitarius (NTS) of the brainstem is a key nucleus for immune-to-brain signalling. It is the main site of termination of vagal afferents and is adjacent to the area postrema, a circumventricular organ allowing blood-borne action of circulating IL-1beta. Although it is well described that IL-1beta activates cerebral endothelial and glial cells, it is still unknown if and how IL-1beta or downstream-synthesized molecules impact NTS synaptic function. In this study we report that IL-1beta did not modulate NTS synaptic transmission per se, whereas prostaglandin E(2) (PGE(2)), which is produced downstream of IL-1beta, produced opposite effects on spontaneous and evoked release. On the one hand, PGE(2) facilitated glutamatergic transmission between local NTS neurons by enhancing the frequency of spontaneous excitatory postsynaptic currents through a presynaptic receptor different from the classical EP1-4 subtypes. On the other hand, PGE(2) also depressed evoked excitatory input from vagal afferent terminals through presynaptic EP3 receptors coupled to G-proteins linked to adenylyl cyclase and protein kinase A activity. Our data show that IL-1beta-induced PGE(2) can modulate evoked and spontaneous release in the NTS differentially through different mechanisms. These data unravel some molecular mechanisms by which innate immune stimuli could signal to, and be integrated within, the brainstem to produce central adaptative responses.
authors.affiliation: Psychoneuroimmunology, Nutrition and Genetics (PsyNuGen), UMR 5226 CNRS-UB2/UMR 1286 INRA-UB2, Université Bordeaux 2, Institut François Magendie, 146 Rue Léo-Saignat, F-33077 Bordeaux, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Marty
authors.forename: Mickaël
authors.initials: M
authors.lastname: El Hachmane
authors.forename: Thierry
authors.initials: T
authors.lastname: Amédée
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000276:immunology; D000818:Animals; D020746:Calcium Channels, L-Type / Q000502:physiology; D020864:Calcium Channels, N-Type / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis / Q000378:metabolism* / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000276:immunology; D019204:GTP-Binding Proteins / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D015213:Neuroimmunomodulation / Q000502:physiology*; D009924:Organ Culture Techniques; D017729:Presynaptic Terminals / Q000276:immunology / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors / Q000378:metabolism; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D017552:Solitary Nucleus / Q000276:immunology* / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology*; D014630:Vagus Nerve / Q000276:immunology / Q000502:physiology
chemical_list: D020746:Calcium Channels, L-Type; D020864:Calcium Channels, N-Type; D017868:Cyclic AMP-Dependent Protein Kinases; D015232:Dinoprostone; D019204:GTP-Binding Proteins; D053583:Interleukin-1beta; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype