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Signaling Mechanisms of Metabotropic Glutamate Receptor 5 Subtype and Its Endogenous Role in a Locomotor Network

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Signaling Mechanisms of Metabotropic Glutamate Receptor 5 Subtype and Its Endogenous Role in a Locomotor Network The Journal of Neuroscience, March 1, 2002, 22(5):1868–1873 Signaling Mechanisms of Metabotropic Glutamate Receptor 5 Subtype and Its Endogenous Role in a Locomotor Network Petronella Kettunen, Patrik Krieger, Dietmar Hess, and Abdeljabbar El Manira Nobel Institute for Neurophysiology, Department of Neuroscience, Retzius Laboratory, Karolinska Institutet, S-171 77 Stockholm, Sweden Metabotropic glutamate receptors (mGluRs) act as modulators depletion of internal Ca 2ϩ stores by thapsigargin but did not in the CNS of vertebrates, but their role in motor pattern gener- involve protein kinase C activation. Furthermore, they were de- 2ϩ 2ϩ ation in particular is primarily unknown. The intracellular signaling pendent on Ca influx, because no [Ca ]i oscillations were mechanisms of the group I mGluRs (mGluR1 and mGluR5), and produced by DHPG in a Ca 2ϩ-free solution or after blockade of their endogenous role in regulating locomotor pattern generation L-type Ca 2ϩ channels. The mGluR5 is activated by an endoge- have been investigated in the spinal cord of the lamprey. Applica- nous release of glutamate during locomotion, and a receptor tion of the group I mGluR agonist (R,S)-3,5-dihydroxyphenylgly- blockade by MPEP caused an increase in the burst frequency. 2ϩ 2ϩ cine (DHPG) produced oscillations of the intracellular Ca con- Thus, our results show that mGluR5 induces [Ca ]i oscillations 2ϩ centration ([Ca ]i) in neurons. The oscillations were blocked by and regulates the activity of locomotor networks through en- the mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine dogenous activation. (MPEP) but not by the mGluR1 antagonist 7-(hydroxyimino)cyclo- 2ϩ propa[b]chromen-1a-carboxylate ethyl ester. These [Ca ]i oscil- Key words: mGluR5; locomotion; spinal cord; modulation; lations were abolished by a phospholipase C blocker and after glutamate; lamprey 2ϩ The generation of coordinated motor patterns involves not only their activation may result in different patterns of the [Ca ]i the fast-acting ionotropic receptors but also the relatively slow response. In expression systems, mGluR1 elicits a single-peaked 2ϩ metabotropic receptors. The role of ionotropic glutamate recep- nonoscillatory [Ca ]i response, whereas mGluR5 elicits oscilla- tors in spinal locomotor networks has been studied extensively tions (Kawabata et al., 1996; Nakanishi et al., 1998). In contrast, (Cazalets et al., 1992; Grillner et al., 1998; Reith and Sillar, 1998; an activation of native mGluR5 in neurons induces different Kiehn et al., 2000). However, there is limited knowledge about cellular effects. In hippocampus neurons, mGluR5 elicits a single- 2ϩ the contribution of metabotropic glutamate receptors (mGluRs) peaked [Ca ]i response (Rae et al., 2000), whereas it induces 2ϩ in locomotor pattern generation. mGluRs with pharmacological [Ca ]i oscillations in the neocortex (Flint et al., 1999). In neu- characteristics corresponding to groups I, II, and III exist in the rons of the subthalamic nucleus, mGluR5 potentiates NMDA lamprey, a lower vertebrate experimental model (Krieger et al., receptor currents (Awad et al., 2000). 1996, 1998; Cochilla and Alford, 1998). Activation of postsynaptic In this study, we investigated which group I mGluR subtype 2ϩ group I mGluRs can increase intracellular calcium concentration mediates the [Ca ]i increase and the underlying intracellular 2ϩ ([Ca ]i), potentiate NMDA-induced responses, and modulate signal transduction pathway. We also compared the pharmacol- the frequency of the locomotor rhythm (Krieger et al., 2000). ogy of this subtype with that inducing the potentiation of NMDA These mGluRs appear not to have a major role in the generation responses. Finally, we examined whether the group I mGluR 2ϩ of the basic locomotor rhythm, but they play a role in its modu- subtype mediating a [Ca ]i increase is endogenously activated lation (Krieger et al., 1998). during locomotion. Our results show that activation of mGluR5 2ϩ This group consists of two receptor subtypes (mGluR1 and induces [Ca ]i oscillations that do not require protein kinase C 2ϩ mGluR5) that elevate the levels of inositol triphosphate (IP3) (PKC) activation, but depend on Ca entry through L-type through the activation of phospholipase C (PLC) (Pin and Du- channels. Thus, in lamprey spinal cord neurons the two subtypes voisin, 1995; Anwyl, 1999; Fagni et al., 2000). Although these two of group I mGluRs have different cellular effects; mGluR1 po- 2ϩ subtypes commonly use a similar signal transduction pathway, tentiates NMDA receptors and mGluR5 induces [Ca ]i oscilla- tions. These two receptor subtypes are activated by endogenous Received July 24, 2001; revised Dec. 4, 2001; accepted Dec. 10, 2001. release of glutamate during locomotion and mediate opposite This work was supported by the Swedish Research Council (project 11562), the effects on the frequency of the locomotor rhythm. Swedish Foundation for Strategic Research, the A. Eriksson Foundation, the Å. Wiberg Foundation, the Swedish Society for Medicine, and the Karolinska Institutet MATERIALS AND METHODS funds. P. Krieger received a fellowship from the Knut and Alice Wallenberg Cell dissociation. Larval lampreys (Petromyzon marinus) were anesthe- Foundation. D.H. received a fellowship from the Deutsche Forschungsgemeinschaft, tized with tricaine methane sulfonate (MS222; 100 mg/l) and the spinal Germany. We thank Drs. S. Grillner, D. Parker, and P. Walle´n for their comments on this manuscript. We are also grateful to H. Axegren and M. Bredmyr for cord was isolated in cooled oxygenated physiological solution. To identify excellent technical assistance. motoneurons (MNs), fluorescein-coupled dextran amine (FDA) was Correspondence should be addressed to A. El Manira, Nobel Institute for Neu- applied before dissociation into muscle tissue along the entire length of rophysiology, Department of Neuroscience, Karolinska Institutet, S-171 77 Stock- the preparation after cutting all dorsal roots to allow the transport of the holm, Sweden. E-mail: [email protected]. dye only through the ventral roots, thus retrogradely labeling MNs. The Copyright © 2002 Society for Neuroscience 0270-6474/02/221868-06$15.00/0 dissociation was performed in Leibovitz’s L-15 culture medium (Sigma, Kettunen et al. • Role of mGluR5 in a Locomotor Network J. Neurosci., March 1, 2002, 22(5):1868–1873 1869 2ϩ Figure 1. DHPG-induced [Ca ]i oscillations in lamprey spinal cord neurons are mediated by MPEP-sensitive, CPCCOEt-insensitive group I mGluRs. A, Images showing an example of 2ϩ [Ca ]i oscillations induced by DHPG in a Fluo- 4/AM-loaded neuron. B, The group I mGluR agonist DHPG (100 ␮M) produced oscillatory 2ϩ [Ca ]i responses, which were elicited by consec- utive applications of the agonist. C,DHPGdid 2ϩ not induce any [Ca ]i oscillations in a neuron preincubated with MPEP (100 ␮M), whereas re- application of DHPG after washout of MPEP 2ϩ produced [Ca ]i oscillations. D, Almost all neu- 2ϩ rons displayed [Ca ]i oscillations in response to DHPG in the control, but fewer responded to DHPG in the presence of MPEP. E, CPCCOEt 2ϩ did not block the oscillatory [Ca ]i response to DHPG. St. Louis, MO) supplemented with penicillin–streptomycin (2 ␮l/ml), determine any relationship between the two experimental conditions. with the osmolarity adjusted to 270 mOsm (El Manira and Bussie`res, The reported p value is double the single-sided p. Fisher’s exact test was 1997). The spinal cord was incubated for 30 min in collagenase (1 mg/ml; performed with an on-line calculator provided by SISA (http://home. Sigma) and then in protease for 45 min (2 mg/ml; Sigma). The tissue was clara.net/sisa/binomial.htm). When the same cells were used as controls subsequently washed with the culture medium and triturated through a and test subjects, the statistical significance was tested with McNemar’s sterilized pipette. The supernatant containing the dissociated cells was test to compare paired groups, performed with an on-line calculator distributed in 10–12 Petri dishes (35 mm) and incubated at 10–12°C for provided by GraphPad (GraphPad Software, San Diego, CA). 1–4d. Electrophysiology. Whole-cell recordings were performed from neurons Calcium imaging. Before calcium imaging, the dissociated cells were in culture using an Axopatch 200A patch-clamp amplifier (Axon Instru- incubated at room temperature for 1–2 hr with Fluo-4/acetoxymethyl ments). The cells were perfused through a gravity-driven multibarreled (AM) (5 ␮M; Molecular Probes, Eugene, OR) added to the medium. The microperfusion system placed close to the recorded cell. Neurons had a same procedure was used to load FDA-labeled MNs with Fluo-4/AM resting membrane potential between Ϫ60 and Ϫ55 mV. The effect of after identification. After removal of the incubation medium, the cells were DHPG was tested in control solution and in the presence of the mGluR1 perfused with a solution containing (in mM): 124 NaCl, 2 KCl, 1.2 MgCl2, antagonist CPCCOEt. The control solution contained (in mM): 124 5CaCl2, 10 glucose, and 10 HEPES, with pH adjusted to 7.6. The following NaCl, 2 KCl, 1.2 MgCl2,5CaCl2, 10 glucose, and 10 HEPES, with pH drugs were tested: (R,S)-3,5-dihydroxyphenylglycine (DHPG), 7-(hydroxy- adjusted to 7.6. For whole-cell recordings, the pipettes were filled with a imino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt), solution containing (in mM): 113 KCH3SO3, 1.2 MgCl2, 10 glucose, and 2-methyl-6-(phenylethynyl)pyridine (MPEP), thapsigargin, 1-(5-isoquino- 10 HEPES, with pH adjusted
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