mGlu1 receptors mediate a post‐tetanic depression at parallel fibre–Purkinje cell synapses in rat cerebellum

Abstract

Metabotropic glutamate (mGlu) receptors are located pre- and postsynaptically at central synapses. Activation of the receptors by exogenous agonists usually results in a reversible depression of fast glutamatergic neurotransmission. Evidence that synaptically released glutamate has such an action, however, is scarce. Sharp microelectrode recordings were used to investigate the modulatory role of mGlu receptors at a well-studied glutamatergic synapse, the one between parallel fibres and Purkinje cells in rat cerebellar slices. Brief, tetanic stimulation of the parallel fibres caused a depression of subsequent fast EPSPs. This post-tetanic depression (PTD) reached its maximum 4.5 s after the tetanus. Measured at this point, PTD was frequency-dependent; 10 stimuli at 20 Hz produced no significant depression, whereas, at 100 Hz the same number of stimuli was maximally effective (approximately 50% depression). The nonselective mGlu antagonist, (S)-alpha-methyl-4-carboxyphenylglycine 1 mm or the GABAB antagonist, CGP35348 (1 mm), both decreased the magnitude of the PTD. In the presence of CGP35348 the mGlu1 antagonist, 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester (300 microm), inhibited PTD further. A group II/III mGlu antagonist had no effect. These observations indicate that synaptically activated mGlu1 receptors not only generate a slow EPSP and induce Ca2+ mobilization in Purkinje cells, as reported previously, but also produce a transient depression of fast synaptic transmission. This short-term plasticity may be important for shaping the output of cerebellar circuits and/or it could provide a substrate for long-term depression when additional mechanisms are superimposed.

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

“…Furthermore, we have characterized this phenomenon in terms of its dependence on the endocannabinoid system. Our work follows the path opened by several recent contributions, which established that the liberation of endocannabinoids by PLC-regulating pathways (both group I mGlu and M 1 /M 3 muscarinic receptors) can be an important mechanism leading to the depression of afferent synaptic inputs (Martin and Alger, 1999;Maejima et al, 2001;Neale et al, 2001;Varma et al, 2001;Robbe et al, 2002;Ohno-Shosaku et al, 2002a, 2003Chevaleyre and Castillo, 2003). Our experiments provide evidence that sustained activation of mGluR1s and CB1Rs triggers a transient modulation of the GABAergic synapses between basket-stellate cells and Purkinje cells.…”

“…Activation of parallel fibers by extracellular stimulation has been shown previously to induce cannabinoid-mediated inhibition of glutamatergic synapses in Purkinje cells Neale et al, 2001;Brown et al, 2003). In contrast to Maejima et al (2001), who used strong stimulation protocols of the parallel fibers to obtain a weak inhibitory effect of the climbing fiber input, Brown et al (2003) reported that more physiological trains of action potentials limited the endocannabinoidmediated effect to the parallel fibers active during stimulation.…”

“…A second pathway involves G-protein-coupled receptors; activation of group I metabotropic glutamate receptors (mGluRs) and of muscarinic receptors can lead to the release of retrogradely active cannabinoids. In the cerebellum, activation of group I mGluRs by a selective agonist (Levenes et al, 2001;Maejima et al 2001) or by sustained parallel fiber (PF) stimulation Neale et al, 2001;Brown et al, 2003) causes a strong inhibition of EPSCs in Purkinje cells that is blocked by cannabinoid receptor antagonists Brown et al, 2003). A similar linkage between exogenously or synaptically activated group I mGluRs and endocannabinoid production has been found in hippocampal CA1 pyramidal neurons (Varma et al, 2001;OhnoShosaku et al, 2002a;Chevaleyre and Castillo, 2003), where also the activation of M 1 and M 3 muscarinic receptor leads to a retrograde modulation of the GABAergic input via endocannabinoid release and CB1R activation (Kim et al, 2002;Ohno-Shosaku et al, 2003).…”

Endocannabinoid‐mediated short‐term synaptic plasticity: depolarization‐induced suppression of inhibition (DSI) and depolarization‐induced suppression of excitation (DSE)

“…A following study showed that activation of group I mGluR receptors, either by application of an exogenous agonist or by repetitive stimulation of parallel fibers, led to a retrograde inhibition of climbing fiber EPSPs , and that these effects were blocked by CB1R antagonists; hence these effects were proposed to be mediated by endocannabinoids. Likewise, brief repetitive stimulation of parallel fibres at high frequency leads to a transient self-inhibition: this was shown to depend on activation of mGluRs (Neale et al, 2001) and, following the development of endocannabinoid research, can now be ascribed to the synthesis and the action of endocannabinoids (Brown et al, 2003).…”

Modulation of GABAergic inhibition in the rat superior colliculus by a presynaptic group II metabotropic glutamate receptor

“…That mGluR activation is dependent on stimulus frequency/intensity has been observed in vitro in other brain areas where short bursts of high-frequency stimulation are necessary in order for the receptors to be activated by the synaptically released endogenous agonist (Scanziani et al 1997;Dube & Marshall, 2000;Mitchell & Silver, 2000;Semyanov & Kullmann, 2000;Neale et al 2001). We attempted to mimic patterns of visual responses with trains of stimuli applied at 20 and 50 Hz, in order to see if this could produce effects which were affected by the group II antagonist LY341495.…”