title: mGluR5 stimulates gliotransmission in the nucleus accumbens.
abstract: Although metabotropic glutamate receptor 5 (mGluR5) is essential for cocaine self-administration and drug-seeking behavior, there is limited knowledge of the cellular actions of this receptor in the nucleus accumbens (NAc). Although mGluR5 has the potential to regulate neurons directly, recent studies have shown the importance of mGluR5 in regulating Ca(2+) signaling in astrocytes and, as a consequence, the Ca(2+)-dependent release of excitatory transmitters from these glia. In this study, we demonstrate that activation of mGluR5 induces Ca(2+) oscillations in NAc astrocytes with the correlated appearance of NMDA receptor-dependent slow inward currents detected in medium spiny neurons (MSNs). Photolysis of caged Ca(2+) loaded specifically into astrocytes evoked slow inward currents demonstrating that Ca(2+) elevations in astrocytes are responsible for these excitatory events. Pharmacological evaluation of these glial-evoked NMDA currents shows that they are mediated by NR2B-containing NMDA receptors, whereas synaptic NMDA receptors rely on NR2A-containing receptors. Stimulation of glutamatergic afferents activates mGluR5-dependent astrocytic Ca(2+) oscillations and gliotransmission that is sustained for minutes beyond the initial stimulus. Because gliotransmission is mediated by NMDA receptors, depolarized membrane potentials exhibited during up-states augment excitation provided by gliotransmission, which drives bursts of MSN action potentials. Because the predominant mGluR5-dependent action of glutamatergic afferents is to cause the sustained activation of astrocytes, which in turn excite MSNs through extrasynaptic NMDA receptors, our results raise the potential for gliotransmission being involved in prolonged mGluR5-dependent adaptation in the NAc.
authors.affiliation: Silvio Conte Center for Integration at the Tripartite Synapse, Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Marcello
authors.initials: M
authors.lastname: D'Ascenzo
authors.forename: Tommaso
authors.initials: T
authors.lastname: Fellin
authors.forename: Miho
authors.initials: M
authors.lastname: Terunuma
authors.forename: Raquel
authors.initials: R
authors.lastname: Revilla-Sanchez
authors.forename: David F
authors.initials: DF
authors.lastname: Meaney
authors.forename: Yves P
authors.initials: YP
authors.lastname: Auberson
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Moss
authors.forename: Philip G
authors.initials: PG
authors.lastname: Haydon
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000378:metabolism / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D018698:Glutamic Acid / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009457:Neuroglia / Q000378:metabolism / Q000502:physiology*; D009714:Nucleus Accumbens / Q000502:physiology*; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D019966:Substance-Related Disorders / Q000503:physiopathology; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: C578936:Grm5 protein, mouse; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D018698:Glutamic Acid; D002118:Calcium