title: Microglia activation triggers astrocyte-mediated modulation of excitatory neurotransmission.
abstract: Fine control of neuronal activity is crucial to rapidly adjust to subtle changes of the environment. This fine tuning was thought to be purely neuronal until the discovery that astrocytes are active players of synaptic transmission. In the adult hippocampus, microglia are the other major glial cell type. Microglia are highly dynamic and closely associated with neurons and astrocytes. They react rapidly to modifications of their environment and are able to release molecules known to control neuronal function and synaptic transmission. Therefore, microglia display functional features of synaptic partners, but their involvement in the regulation of synaptic transmission has not yet been addressed. We have used a combination of pharmacological approaches with electrophysiological analysis on acute hippocampal slices and ATP assays in purified cell cultures to show that activation of microglia induces a rapid increase of spontaneous excitatory postsynaptic currents. We found that this modulation is mediated by binding of ATP to P2Y1R located on astrocytes and is independent of TNFα or NOS2. Our data indicate that, on activation, microglia cells rapidly release small amounts of ATP, and astrocytes, in turn, amplified this release. Finally, P2Y1 stimulation of astrocytes increased excitatory postsynaptic current frequency through a metabotropic glutamate receptor 5-dependent mechanism. These results indicate that microglia are genuine regulators of neurotransmission and place microglia as upstream partners of astrocytes. Because pathological activation of microglia and alteration of neurotransmission are two early symptoms of most brain diseases, our work also provides a basis for understanding synaptic dysfunction in neuronal diseases.
authors.affiliation: Institut de Biologie de l'Ecole Normale Supérieure, F-75005 Paris, France. olivier.pascual@biologie.ens.fr
authors.forename: Olivier
authors.initials: O
authors.lastname: Pascual
authors.forename: Sarrah
authors.initials: S
authors.lastname: Ben Achour
authors.forename: Philippe
authors.initials: P
authors.lastname: Rostaing
authors.forename: Antoine
authors.initials: A
authors.lastname: Triller
authors.forename: Alain
authors.initials: A
authors.lastname: Bessis
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D015153:Blotting, Western; D017931:DNA Primers / Q000235:genetics; D004594:Electrophysiology; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000502:physiology*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D060888:Real-Time Polymerase Chain Reaction; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D058472:Receptors, Purinergic P2Y1 / Q000378:metabolism
chemical_list: D017931:DNA Primers; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D058472:Receptors, Purinergic P2Y1; D000255:Adenosine Triphosphate