title: Microglia-derived purines modulate mossy fibre synaptic transmission and plasticity through P2X4 and A1 receptors.
abstract: Recent data have provided evidence that microglia, the brain-resident macrophage-like cells, modulate neuronal activity in both physiological and pathophysiological conditions, and microglia are therefore now recognized as synaptic partners. Among different neuromodulators, purines, which are produced and released by microglia, have emerged as promising candidates to mediate interactions between microglia and synapses. The cellular effects of purines are mediated through a large family of receptors for adenosine and for ATP (P2 receptors). These receptors are present at brain synapses, but it is unknown whether they can respond to microglia-derived purines to modulate synaptic transmission and plasticity. Here, we used a simple model of adding immune-challenged microglia to mouse hippocampal slices to investigate their impact on synaptic transmission and plasticity at hippocampal mossy fibre (MF) synapses onto CA3 pyramidal neurons. MF-CA3 synapses show prominent forms of presynaptic plasticity that are involved in the encoding and retrieval of memory. We demonstrate that microglia-derived ATP differentially modulates synaptic transmission and short-term plasticity at MF-CA3 synapses by acting, respectively, on presynaptic P2X4 receptors and on adenosine A1 receptors after conversion of extracellular ATP to adenosine. We also report that P2X4 receptors are densely located in the mossy fibre tract in the dentate gyrus-CA3 circuitry. In conclusion, this study reveals an interplay between microglia-derived purines and MF-CA3 synapses, and highlights microglia as potent modulators of presynaptic plasticity.
authors.affiliation: Interdisciplinary Institute for Neuroscience, CNRS UMR 5297, University of Bordeaux, Bordeaux, France.|CNC Centre for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.|Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Jimmy
authors.initials: J
authors.lastname: George
authors.affiliation: CNC Centre for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.|Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Cunha
authors.affiliation: Interdisciplinary Institute for Neuroscience, CNRS UMR 5297, University of Bordeaux, Bordeaux, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Mulle
authors.affiliation: Interdisciplinary Institute for Neuroscience, CNRS UMR 5297, University of Bordeaux, Bordeaux, France.|IINS, UMR 5297 CNRS - Université de Bordeaux, Bordeaux Cedex, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Amédée
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001081:Apyrase / Q000494:pharmacology; D002478:Cells, Cultured; D019706:Excitatory Postsynaptic Potentials; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D019599:Mossy Fibers, Hippocampal / Q000187:drug effects / Q000502:physiology*; D009473:Neuronal Plasticity / Q000187:drug effects; D058911:Purinergic P2X Receptor Agonists / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D058848:Receptors, Purinergic P2X4 / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects
chemical_list: C092431:6-N,N-diethyl-beta,gamma-dibromomethylene-D-ATP; D008070:Lipopolysaccharides; D058911:Purinergic P2X Receptor Agonists; D011687:Purines; D058848:Receptors, Purinergic P2X4; C058394:2-chloro-N(6)cyclopentyladenosine; D000255:Adenosine Triphosphate; D001081:Apyrase; D000241:Adenosine
keywords: A1 receptor; P2X4 receptor; hippocampal synaptic plasticity; microglia; purines