Postsynaptic Current Mediated by Metabotropic Glutamate Receptors in Cerebellar Purkinje Cells

Abstract

In rat cerebellar slices, repetitive parallel fiber stimulation evokes an inward, postsynaptic current in Purkinje cells with a fast component mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptors and a slower component mediated by metabotropic glutamate receptors (mGluR). The mGluR-mediated excitatory postsynaptic current (mGluR-EPSC) is evoked selectively by parallel fiber stimulation; climbing fiber stimulation is ineffective. The mGluR-EPSC is elicited most effectively with increasing frequencies of parallel fiber stimulation, from a threshold of 10 Hz to a maximum response at approximately 100 Hz. The amplitude of the mGluR-EPSC is a linear function of the number of stimulus pulses without any apparent saturation, even with >10 pulses. Thus mGluRs at the parallel fiber-Purkinje cell synapse can function as linear detectors of the number of spikes in a burst of activity in parallel fibers. The mGluR-EPSC is present from postnatal day 15 and persists into adulthood. It is inhibited by the generic mGluR antagonist (RS)-a-methyl-4-carboxyphenylglycine and by the group I mGluR antagonist (RS)-1-aminoindan-1,5-dicarboxylic acid at a concentration selective for mGluR1. Although the intracellular transduction pathway involves a G protein, the putative mediators of mGluR1 (phospholipase C and protein kinase C) are not directly involved, indicating that the mGluR-EPSC studied here is mediated by a different and still unidentified second-messenger pathway. Heparin, a nonselective antagonist of inositol-trisphosphate (IP3) receptors, has no significant effect on the mGluR-EPSC, suggesting that also IP3 might be not required for the response. Buffering intracellular Ca2+ with a high concentration of bis-(o-aminophenoxy)-N,N,N', N'-tetraacetic acid partially inhibits the mGluR-EPSC, indicating that Ca2+ is not directly responsible for the response but that resting Ca2+ levels exert a tonic potentiating effect on the mGluR-EPSC.

Group I Metabotropic Glutamate Receptors Inhibit GABA Release at Interneuron-Purkinje Cell Synapses through Endocannabinoid Production

“…Parallel fibers were stimulated via an electrode placed in the molecular layer. We first verified that brief trains of parallel fiber stimulation elicited a mGluR1-activated slow EPSC in Purkinje cells (Batchelor et al, 1994;Tempia et al, 1998) (Fig. 7B).…”

“…DHPG induced three distinct events: (1) a transient inward current, which reflects the opening of cationic channels activated by mGluR1s in Purkinje cells (Batchelor et al, 1994;Tempia et al, 1998;Kim et al, 2003); (2) an increase of frequency of sIPSCs (Llano and Marty, 1995), likely through direct activation of mGluR1s and mGluR5s (Baude et al, 1993;Negyessy et al, 1997) on molecular layer interneurons; and (3) a marked decrease of the eIPSCs (Fig. 1 A).…”

“…4 Aa). The mGluR1-triggered inward current represents a good test for G-protein functionality, because it is known to depend on G-protein activation in Purkinje cells (Tempia et al, 1998;Canepari and Ogden, 2003).…”

Ca 2+ activity at GABA B receptors constitutively promotes metabotropic glutamate signaling in the absence of GABA

“…Given that Ca o 2ϩ -GABA B R interaction does not trigger diffusible G protein signaling (12), Ca o 2ϩ activity at GABA B R is likely to influence a local target(s). A possible target is metabotropic glutamate receptor 1 (mGluR1) (15,16), which is expressed in many central neurons and mediates slow postsynaptic potentials (17,18), intracellular Ca 2ϩ mobilization (19)(20)(21), synaptic plasticity (22)(23)(24)(25), and developmental synapse elimination (24,26). In cerebellar Purkinje cells, mGluR1 colocalizes with GABA B R at the annuli of the dendritic spines innervated by excitatory parallel fibers (7,27).…”

Control of neuronal excitability by Group I metabotropic glutamate receptors

“…In the cerebellum, glutamate released from parallel fiber synapses onto Purkinje cells causes a slow EPSC mediated by mGlu receptors and G proteins (Hirono et al 1998(Hirono et al , 2001Tempia et al 1998). This current can be mimicked by ACPD or DHPG (Hartmann et al 2008), but unlike other Group Imediated responses is resistant or partially resistant to strong intracellular Ca 2+ buffering (BAPTA), inhibition of PLC (U-73122), and inhibition of PKC.…”