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. 2003 Jan 1;23(1):122-30.
doi: 10.1523/JNEUROSCI.23-01-00122.2003.

Distinct functional roles of the metabotropic glutamate receptors 1 and 5 in the rat globus pallidus

Olga V Poisik  1 , Guido Mannaioni, Stephen Traynelis, Yoland Smith, P Jeffrey Conn
Affiliations

Distinct functional roles of the metabotropic glutamate receptors 1 and 5 in the rat globus pallidus

Olga V Poisik et al. J Neurosci. .

Abstract

Group I metabotropic glutamate receptors (mGluRs) 1 and 5 frequently colocalize in the same neurons throughout the CNS. Because both receptors can couple to the same effector systems, the purpose of their cellular coexpression remains unclear. Here, we report that group I mGluR1 and mGluR5 have distinct functional roles in type II neurons of the rat globus pallidus (GP). Type II GP neurons form a large population of GABAergic projection neurons that are characterized by the presence of inwardly rectifying current I(h), low-threshold voltage-activated calcium current I(t), and activity at rest. Although immunocytochemical analysis reveals a high degree of neuronal colocalization of the two group I mGluRs in the GP, activation of mGluR1 only directly depolarizes type II GP neurons. Interestingly, blockade of mGluR5 by a highly selective antagonist, methylphenylethynylpyridine, leads to the potentiation of the mGluR1-mediated depolarization in this neuronal subpopulation. Metabotropic GluR1 desensitizes during repeated activation with the agonist in type II GP neurons, and blocking mGluR5 prevents the desensitization of the mGluR1-mediated depolarization. Elimination of the activity of protein kinase C (PKC) by an application of 1 microm bisendolylmaleimide or 1 microm chelerythrine, both protein kinase C inhibitors, potentiates the mGluR1-mediated response and prevents the desensitization of mGluR1 in type II GP neurons, suggesting that the effect of mGluR5 on mGluR1 signaling may involve PKC. Together, these data illustrate a novel mechanism by which mGluR1 and mGluR5, members of the same family of G-protein-coupled receptors, can interact to modulate neuronal activity in the rat GP.

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Figures

Fig. 1.
Fig. 1.
Electrophysiological and morphological profiles of type I and type II GP neurons. A, Type I GP neurons are characterized by the presence of a ramp-like depolarization during a depolarizing current injection, lack of time- and voltage-dependent current Ih, and low input resistance.B, Type II GP neurons are characterized by lack of ramp depolarization during a depolarizing current injection, presence of time- and voltage-dependent currentIh, activity at rest, the presence of rebound depolarization after a hyperpolarizing step, and high input resistance. C, No consistent differences in cellular morphology are observed between type I (i) and type II (ii) GP neurons. D, No consistent differences in the position of cell body or dendritic arborization were observed between type I (i) and type II (ii) GP neurons.Str, Striatum; GP, globus pallidus;D, dorsal; P, posterior. Scale bars: C, 20 μm; D, 100 μm.
Fig. 2.
Fig. 2.
mGluR1a and mGluR5 are colocalized in rat GP neurons. A, Low-power micrograph of mGluR1a immunoreactivity in the GP. B, High-power micrograph of the same field showing neuronal cell bodies immunoreactive for both mGluR1a (i) and mGluR5 (ii). Str, Striatum;GP, globus pallidus. Scale bars: A, 200 μm; B, 15 μm.
Fig. 3.
Fig. 3.
Activation of mGluR1 depolarizes type I GP neurons. A, Type I GP neurons are depolarized by 30 μm DHPG, a group I-selective agonist, whereas group II- and III-selective agonists LY354740 and l-AP-4, respectively, do not change the membrane potential in these cells.B, Mean ± SEM of data for type I GP neurons;number of cells per condition is given above eachbar in parentheses. *p > 0.05, denotes statistical significance and difference compared with DHPG as determined by one-factor ANOVA and Tukey's pairwise comparison procedure. C, The DHPG-induced depolarization is predominantly mediated by mGluR1 in type I GP neurons. Preincubation with 100 μm LY373685, an mGluR1-selective blocker, significantly reduced the amplitude of the DHPG-induced depolarization. However, a preincubation with both 100 μm LY373685 and 10 μm MPEP, an mGluR5-selective antagonist, completely blocked the response to DHPG.D, Mean ± SEM of data for type I GP neurons;number of cells per condition is given above eachbar in parentheses. *p > 0.05, denotes statistical significance and difference compared with DHPG as determined by one-factor ANOVA and Tukey's pairwise comparison procedure. TTX (0.5 μm) was bath applied for at least 5 min before the beginning of all experiments. All antagonists were bath applied for 10 min before exposure to DHPG.
Fig. 4.
Fig. 4.
Pharmacology of group I-mediated depolarization in type II GP neurons. A, Activation of the group I mGluRs with 30 μm DHPG causes a depolarization and reduces the input resistance in type II GP neurons, whereas group II- and III-selective agonists LY354740 and l-AP-4, respectively, do not change the membrane potential or the input resistance in these cells. B, Mean ± SEM of data for type II GP neurons; number of cells per condition is given above each bar in parentheses. *p > 0.05, denotes statistical significance and difference compared with DHPG as determined by one-factor ANOVA and Tukey's pairwise comparison procedure. C, Dose–response relationship for DHPG-induced depolarization in type II GP neurons. D, MGluR1 solely mediates DHPG-induced depolarization in type II GP neurons. Preincubation with the mGluR1-selective antagonist LY363785 abolishes the DHPG-induced depolarization, whereas preincubation with MPEP, an mGluR5-selective blocker, potentiates the response to DHPG. E, Mean ± SEM for type II GP neurons; number of cells per condition is given above each bar inparentheses. *p > 0.05, denotes statistical significance and difference compared with DHPG as determined by one-factor ANOVA and Tukey's pairwise comparison procedure.
Fig. 5.
Fig. 5.
DHPG-induced current reverses polarity at two membrane potentials in type II GP neurons. The group I-mediated depolarization observed in type II GP neurons is associated with an increase in membrane conductance (Fig. 4A). This increase in membrane conductance is evident in the whole-cell current–voltage relationship shown. The inset shows the subtraction of the currents that reveals a V-shaped relationship with two distinct potentials, at which the current polarity is reversed (see also dotted boxes 1 and 2). Axis titles apply in the inset. This figure is representative of results observed in four cells.
Fig. 6.
Fig. 6.
Blockade of mGluR5 prevents the desensitization of the mGluR1-mediated depolarization in type II GP neurons. mGluR1-mediated depolarization desensitizes during repeated application of 100 μm DHPG (A, top trace). Pretreatment with 10 μm MPEP, an mGluR5-selective antagonist, for 10 min before the first application of 100 μm DHPG prevents the desensitization of the mGluR1-mediated depolarization (A, bottom trace). B, Mean ± SEM of data for five type II GP neurons per condition. *p > 0.05, denotes statistical significance and difference between responses to second or third application of DHPG for control (no MPEP) and 10 μm MPEP as determined by two-factor repeated-measures ANOVA and Tukey's pairwise comparison procedure. Barsabove each trace indicate timed applications of 100 μm DHPG above the cell body.
Fig. 7.
Fig. 7.
PKC regulates mGluR1 response to DHPG in type II GP neurons. A, B, Blockade of PKC with 1 μm Bis or 1 μm Chel potentiates mGluR1-mediated depolarization, whereas activation of PKC with 10–100 nm PMA reduces it. Bis, Chel, PMA, or 4-α-PMA were included in the intracellular solution and allowed to diffuse into the cell for 10 min before the bath application of DHPG. B, Mean ± SEM of data for type II GP neurons; number of cells per condition is given above each bar inparentheses. *p > 0.05, denotes statistical significance and difference compared with DHPG as determined by one-factor ANOVA and Tukey's pairwise comparison procedure. C, D, The effects of Bis and MPEP are not additive. PMA still has an effect on the mGluR1-mediated response to DHPG in the presence of MPEP. D, Mean ± SEM of data for type II GP neurons; number of cells per condition is given above each bar inparentheses. *p > 0.05, denotes statistical significance and difference compared with DHPG as determined by one-factor ANOVA and Tukey's pairwise comparison procedure.
Fig. 8.
Fig. 8.
PKC regulates the desensitization of mGluR1 in type II GP neurons. Metabotropic GluR1-mediated depolarization desensitizes during repeated activation with 100 μm DHPG (A, top trace). In the presence of 1 μm Bis, a PKC blocker, which was included in the intracellular solution and allowed to diffuse into the cell for 10 min before the first application of 100 μm DHPG, the desensitization of the mGluR1-mediated depolarization is prevented (A, bottom trace). B, Mean ± SEM of data for four type II GP neurons per condition. *p > 0.05, denotes statistical significance and difference between responses to second or third application of DHPG for control (no Bis) and 1 μm Bis as determined by two-factor repeated-measures ANOVA and Tukey's pairwise comparison procedure.Bars above each trace indicate timed applications of 100 μm DHPG above the cell body.
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References

    1. Alagarsamy S, Marino MJ, Rouse ST, Geraeau IVRW, Heinemann SF, Conn PJ. Activation of NMDA receptors reverses desensitization of mGluR5 in native and recombinant systems. Nat Neurosci. 1999;2:234–240. - PubMed
    1. Alagarsamy S, Sorensen SD, Conn PJ. Coordinate regulation of metabotropic glutamate receptors. Curr Opin Neurobiol. 2001;11:357–362. - PubMed
    1. Anwyl R. Metabotropic glutamate receptors: electrophysiological properties and role in plasticity. Brain Res Brain Res Rev. 1999;29:83–120. - PubMed
    1. Awad H, Hubert GW, Smith Y, Levey AI, Conn PJ. Activation of metabotropic glutamate receptor 5 has direct excitatory effects and potentiates NMDA receptor currents in neurons of the subthalamic nucleus. J Neurosci. 2000;20:7871–7879. - PMC - PubMed
    1. Bradley SR, Marino MJ, Wittmann M, Rouse ST, Awad H, Levey AI, Conn PJ. Activation of group II metabotropic glutamate receptors inhibits synaptic excitation of the substantia nigra pars reticulata. J Neurosci. 2000;20:3085–3094. - PMC - PubMed

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