Regulation of synaptic transmission in the mossy fibre-granule cell pathway of rat cerebellum by metabotropic glutamate receptors

Abstract

The role of metabotropic glutamate receptors (mGluRs) in the mossy fibre-granule cell pathway in rat cerebellum was studied using slice preparations and electrophysiological techniques. Application of the group I selective agonist ( S)-3,5-dihydroxyphenylglycine (DHPG) evoked, in a concentration-dependent manner (EC 50=33 μM), a depolarising/hyperpolarising complex response from granule cells which was preferentially inhibited by the group I selective antagonist ( S)-4-carboxyphenylglycine (4CPG). The group III selective agonist l-amino-4-phosphonobutyrate (AP4) evoked a hyperpolarising response (EC 50=10 μM) which was inhibited by the group II/III selective antagonist ( S)-α-methyl-4-phosphonophenylglycine (MPPG). The group II agonist (2 S,2′ R,3′ R)-2-(2′,3′-dicarboxylcyclopropyl)glycine (DCG-IV) elicited no measurable voltage change. The amplitude of the synaptically-mediated mossy fibre response in granule cells was unaffected during application of AP4, was reduced by DHPG and was enhanced by DCG-IV (EC 50=80 nM). These effects were inhibited by the group selective antagonists 4CPG and (2 S,1′ S,2′ S,3′ R)-2-(2′-carboxy-3′-phenylcyclopropyl)glycine (PCCG-4), respectively. Further investigation using patch-clamp recording revealed that DCG-IV potently inhibited spontaneous GABAergic currents. We conclude that group I and III (but not group II) mGluRs are functionally expressed by granule cells, whereas unexpectedly group II or III mGluRs do not appear to be present presynaptically on mossy fibre terminals. Group II mGluRs are located on Golgi cell terminals; when activated these receptors cause disinhibition, a function which may be important for gating information transfer from the mossy fibres to the granule cells.