Pharmacology of the metabotropic GluR-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 ofmGluR1. The distribution of mGluR types in the climbing fiber (CF) to PC synapses is not well known. Only recently an mGluR1-mediated all-or-none post-synaptic current was also demonstrated at the CF-PC synapse (Dzubay & Otis, Neuron 2002; 36: 1159). Using whole cell patch-clamp recordings from PCs in rat cerebellar slices with AMPA receptors blocked(NBQX, 10 or CNQX, 20mM) and impaired glutamate uptake (TBOA, 100 mM) we demonstrate a more complex pharmacology of a current obtained by single or train (10 or 100 Hz) CF stimulation. The mGluR1 specific antagonist CPCCOEt, 100 mM 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. In addition, 100 mM MSOP did not occlude the inhibition by 0.2 mM LY341495. The ambiguous effect of CPCCOEt was checked by measuring the paired-pulse depression of the CF EPSC, which was not changed with the antagonist. The paired-pulse plasticity was also not changed by CPCCOEt in low (0.5mM) external Ca2+ (used to prevent saturation of AMPARs), thus excluding a presynaptic effect. However, CPCCOEt induced arise in the amplitude (by 25%) as well as a prolongation of the decay time of CF EPSCs at normal 2mM Ca2+, i.e. under conditions of AMPAR saturation (11.7 ± 0.7 ms vs. 15.8 ± 1.5 ms), thus indicating an effect of postsynaptic origin. In 0.5 mM Ca2+ the decay of CF EPSCs was faster (7.5 ± 1.2 ms) but it was also prolonged by CPCCOEt (8.8 ± 1.2 ms). However, the CF EPSC amplitude was not significantly affected indicating an underlying Ca2 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 Ca2 i. The additional electrophysiological role of mGluR II & III types was also indicated. Such a complex regulatory mechanism may have an important role in them GluR-dependent forms of homosynaptic plasticity and motor learning at the CF-PC synapse.
Citation : Anjus, P.R., Zhu. L., Strata, P. (2003) Pharmacology of the metabotropic GluR-mediated current at the climbing fiber to Purkinje cell synapse. Creating Coordination in the Cerebellum, Catania, October, 2003, The Cerebellum, 3, pp. 39.
Research Institute : Leicester Institute for Pharmaceutical Innovation - From Molecules to Practice (LIPI)
Peer Reviewed : No