THE GLUTAMATE UPTAKE INHIBITOR L-TRANS-PYRROLIDINE-2,4-DICARBOXYLATE DEPRESSES EXCITATORY SYNAPTIC TRANSMISSION VIA A PRESYNAPTIC MECHANISMIN CULTURED HIPPOCAMPAL-NEURONS

Sodium-dependent high-affinity uptake of glutamate is thought to play a major role in the maintenance of very low extracellular concentratio ns of excitatory amino acids (EAA), and may modulate the actions of re leased transmitter at G-protein-coupled receptors and extrasynaptic re ceptors that are activated over a longer distance and time course. We have examined the effects of the recently developed uptake inhibitor L -trans-pyrrolidine-2,4-dicarboxylate (L-trans-PDC) on monosynaptically evoked excitatory postsynaptic currents (EPSCs) in very-low-density c ultures of hippocampal neurons. L-Trans-PDC produced a decreased ampli tude of both the non-NMDA and NMDA receptor-mediated components of mon osynaptically evoked EPSCs. Examination of miniature EPSCs (mEPSCs) in dicated that changes in the sensitivity of postsynaptic non-NMDA recep tors did not underlie the decrease in evoked EPSC amplitudes. The meta botropic receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) also depressed both components of the EPSC. The com petitive metabotropic receptor antagonist (RS)-alpha-methyl-4-carboxyp henylglycine (MCPG) blocked the depression of EPSC amplitude induced b y 1S,3R-ACPD and also blocked the effects of L-trans-PDC. Finally, low concentrations of L-glutamate (2 mu M) mimicked the effects of L-tran s-PDC on EPSC amplitude. From these results we conclude that the appli cation of L-trans-PDC to cultured hippocampal neurons results in the a ctivation of presynaptic metabotropic receptors, leading to a decrease in synaptic transmission. We propose that this effect is due to an in crease in ambient glutamate concentrations following inhibition of glu tamate uptake, resulting in presynaptic inhibition of excitatory synap tic transmission.