Group II and III metabotropic glutamate receptors modulate paired pulse depression in the rat dentate gyrus in vitro

We have investigated the effect of a number of group I, II and III metabotropic glutamate (mGlu) receptor agonists and antagonists on paired pulse depression in the medial perforant path of the rat dentate gyrus in vitro. A triphasic pattern of a large depression at short intervals (10-50 ms), a reduction of this depression at intermediate intervals (50-200 ms) and again a large depression at late intervals (200 ms) was observed. The group I mGlu receptor agonist, (S)-3,5-dihydroxy phenylglycine ((S)-DHPG; 20 microM) had no significant effect on paired pulse depression at any interstimulus intervals. The mGlu receptor group II and III agonists, L-CCG-1 ((2S,3S,4S)-alpha-(carboxy-cyclopropyl)-glycine), DCG-IV ((2S,1'R,2'R,3'R)-2-2',3'-dicarboxy cyclopropylglycine), 1S,3R-ACPD (1S,3R-1-aminocyclopentate-1,3-dicarboxylic acid) and L-AP4 (L-2-amino-4-phosphono butyric acid) reduced paired pulse depression at interstimulus intervals of 200 ms or less. Application of the non specific mGlu receptor antagonist, MCPG (alpha-methyl carboxy-phenylglycine; 200 microM) completely inhibited the 1S,3R ACPD-induced reduction in paired pulse depression but was without effect on the L-AP4 response. The relatively specific group II antagonist MCCG ((2S,3S,4S)-2-methyl-2-carboxy cycloproprylglycine) at 200 microM and 500 microM, attenuated but did not completely inhibit the DCG-IV induced reduction of paired pulse depression. The putative group III pre-synaptic mGlu receptor antagonist alpha-methyl-L-AP4 and MSOP ((RS)-alpha-methylserine-O-phosphate) both at 200 microM inhibited the L-AP4-induced reduction in paired pulse depression at intermediate phase interstimulus intervals but not at early interstimulus intervals. These results specifically demonstrate the involvement of group III and III mGlu receptor ligands in the modulation of paired pulse depression in the medial perforant pathway.