Pharmacology of the metabotropic glutamate receptor mediated current at the climbing fiber to Purkinje cell synapse

Different forms of synaptic plasticity in the cerebellum are mediated by metabotropic glutamate receptors (mGluRs). At parallel fiber (PF) to Purkinje cell (PC) synapses activation of mGluR gives rise to a well known slow synaptic current inhibited by antagonists of mGluR1. The distribution of mGluR types in the climbing fiber (CF) to PC synapses is not well known. However, a mGluR1alpha-mediated all-or-none postsynaptic current was also demonstrated at the CF-PC synapse (Dzubay and Otis, Neuron 36, 1159, 2002). Using whole cell patch-clamp recording from PCs in rat cerebellar slices with AMPA receptors blocked and glutamate uptake impaired we demonstrate a more complex pharmacology of a current obtained by single or train CF stimulation. The mGluR1 specific antagonist CPCCOEt in a group of cells suppressed this response while in a similar number of other cells it induced a potentiating effect. The antagonists of mGluR groups II and III (LY341495 and MSOP, respectively) predominantly suppressed the current. The ambiguous effect of CPCCOEt was checked by measuring the paired-pulse depression of the CF EPSC, which was not changed with the antagonist in normal as well as in low (0.5 mM) external Ca(2+) (used to prevent saturation of AMPARs), thus excluding a presynaptic effect. However, CPCCOEt induced a rise in the amplitude (by approximately 50%) as well as a prolongation (p<0.05) of the decay time of CF EPSCs at normal 2 mM Ca(2+), i.e. under conditions of AMPAR saturation, thus indicating an effect of postsynaptic origin. In 0.5 mM Ca(2+) the decay of CF EPSCs was longer but it was also significantly prolonged (p?0.01) by CPCCOEt. However, the CF EPSC amplitude was not significantly affected indicating an underlying Ca(2+)-dependent mechanism. Thus, the pharmacology of the PC mGluR-mediated response points to a dual postsynaptic role of mGluR1 giving rise to a slow postsynaptic current but also regulating other presumably mGluR-dependent currents via second messenger molecules and Ca(2+). The additional electrophysiological role of mGluR II III types was also indicated. Such a complex regulatory mechanism may have an important role in the mGluR-dependent forms of homosynaptic plasticity and motor learning at the CF-PC synapse.