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.addiction ͉ astrocytes ͉ glutamate release ͉ NMDA receptors A lthough the dopaminergic system is known to play important roles in responses to drugs of abuse, there is an increasing awareness of the importance of glutamate in mediating effects of these drugs in the brain (1). Cocaine administration requires glutamatergic transmission in the nucleus accumbens (NAc) for drug-seeking behavior (2, 3) with accumulating evidence demonstrating the importance of metabotropic glutamate receptors (mGluRs) in mediating the actions of extracellular glutamate after cocaine use (4). mGluR5 knockout mice do not acquire cocaine self-administration behavior (4), and in wild-type mice the mGluR5 antagonist, 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP), decreases cocaine, morphine, and nicotine selfadministration and drug-seeking behavior (5-8).Although astrocytes are electrically inexcitable, emerging evidence demonstrates that these nonneuronal cells respond to neurotransmitters with elevations in their internal Ca 2ϩ and with the release of the chemical transmitters glutamate, ATP and D-serine (9, 10). Because astrocytes and neurons release common chemical transmitters, we use the term gliotransmitter and gliotransmission to refer to their release from astrocytes (11). Recent...

Supportive or information-processing functions of the mature protoplasmic astrocyte in the mammalian CNS? A critical appraisal

“…The data to date provides convincing evidence that vesicular release of glutamate can be obtained under some conditions, leading to increased EPSC frequency in granule cell neurons in the dentate of the rat hippocampus (Jourdain et al, 2007) and induction of a slow inward current (SIC) that increases action potential firing in the target neuron in the nucleus accumbens (D'Ascenzo et al, 2007). The SIC has been attributed to glutamate acting on NR2B subunit-containing extrasynaptic NMDA receptors (Fellin et al, 2004;D'Ascenzo et al, 2007).…”

“…Increases in intracellular Ca 2+ in astrocytes in response to neuronal stimulation have several effects on synaptic activity (Perea and Araque, 2007), and increased sensory input also results in increased intracellular Ca 2+ (Perea and Araque, 2005b;Wang et al, 2006). The data to date provides convincing evidence that vesicular release of glutamate can be obtained under some conditions, leading to increased EPSC frequency in granule cell neurons in the dentate of the rat hippocampus (Jourdain et al, 2007) and induction of a slow inward current (SIC) that increases action potential firing in the target neuron in the nucleus accumbens (D'Ascenzo et al, 2007). The SIC has been attributed to glutamate acting on NR2B subunit-containing extrasynaptic NMDA receptors (Fellin et al, 2004;D'Ascenzo et al, 2007).…”

“…In a systematic developmental study we found progressive changes in the expression of these electrophysiological phenotypes, with the cells that give linear I-V curves representing ~90% of the recorded glia after 21 days . Such linear (passive) I-V curves are now being used as diagnostic of mature astrocytes before studying other aspects (D'Ascenzo et al, 2007;Perea and Araque, 2007;Jourdain et al, 2007). Post-recording staining of smaller representative groups showed that these cells were all GLAST(+) astrocytes, whereas the two nonlinear phenotypes shown in Fig.…”

Contribution of Cystine–Glutamate Antiporters to the Psychotomimetic Effects of Phencyclidine

“…These transporters are active in clearing glutamate released from cystineglutamate exchange (Baker et al, 2002), and prevents glutamate maintained by nonvesicular release to access synaptic receptors (Jabaudon et al, 1999). To the extent that NR2B receptors are located outside the synapse, this hypothesis is supported by the recent observation that glutamate release from astrocytes appears to stimulate extrasynaptic, but not synaptic NMDA receptors (D'Ascenzo et al, 2007). The existence of multiple pools may partially account for the ambiguity regarding the contribution of glutamate to schizophrenia in which both increased and decreased glutamate signaling have been hypothesized (Moghaddam and Adams, 1998;Barch et al, 2001;MacDonald et al, 2005).…”

Enhanced Astrocytic Ca2+Signals Contribute to Neuronal Excitotoxicity after Status Epilepticus

“…1 E). mGluR5 mediates enhanced astrocytic calcium signals after SE Because metabotropic glutamate receptors, and mGluR5 in particular, contribute to astrocytic Ca 2ϩ signals in brain slices (Pasti et al, 1997;Parri et al, 2001;Bowser and Khakh, 2004;D'Ascenzo et al, 2007), we asked whether mGluR5 mediates the enhanced astrocytic Ca 2ϩ signaling detected after SE. Anti-mGluR5 immunoreactivity showed colocalization with cortical astrocytes in GFAP-GFP transgenic mice raising the potential for direct mGluR5-mediated control of astrocytic Ca 2ϩ signals (supplemental Fig.…”