SYNAPTIC ACTIVATION OF METABOTROPIC GLUTAMATE RECEPTORS IN THE PARALLEL FIBER-PURKINJE CELL PATHWAY IN RAT CEREBELLAR SLICES

Glutamate, the major excitatory neurotransmitter in the central nervou s system, acts through two broad classes of receptors: ion channel-Lin ked (ionotropic) receptors, which include N-methyl-D-aspartate and lph a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, and me tabotropic receptors which couple via G-proteins to intracellular mess enger cascades. Seven subtypes of mGluR are known to exist(21) but the ir roles in synaptic physiology are poorly understood. In cerebellar P urkinje cells, application of the mGluR agonist, trans-1-aminocyclopen tane-1,3-dicarboxylic acid, or the active enantiomer, 1S,3R-ACPD, resu lts in a depolarization associated with an inward current(7,26) and an elevation of intracellular Ca2+ (for review see Ref. 29). Moreover, u sing an extracellular (grease-gap) technique that monitors population responses, we have previously discovered that, in Purkinje cells of ad ult rat cerebellum, brief tetanic stimulation of the glutamatergic par allel fibre input gives rise to a slow depolarising synaptic potential that is resistant to ionotropic glutamate receptor blockers and to an tagonists acting at GABA receptors.(2) It was suggested that this nove l potential is mediated by metabotropic receptors. The advent of antag onists for metabotropic receptors(4) has allowed us to test this hypot hesis. We find that the S-enantiomer of alpha-methyl-4-carboxyphenylgl ycine stereoselectively antagonizes the slow synaptic potential record ed using the grease-gap method. The results were confirmed by intracel lular recording from Purkinje cells. To our knowledge this is the firs t direct evidence of an mGluR-mediated EPSP in intact brain tissue.