DIFFERENTIAL INVOLVEMENT OF GROUP-II AND GROUP-III MGLURS AS AUTORECEPTORS AT LATERAL AND MEDIAL PERFORANT PATH SYNAPSES

1. Previous reports have shown that group III metabotropic glutamate r eceptors (mGluRs) serve as autoreceptors at the lateral perforant path , but to date there has been no rigorous determination of the roles of other mGluRs as autoreceptors at this synapse. Furthermore, it is not known which of the the mGluR subtypes serve as autoreceptors at the m edial perforant path synapse. With the use of whole cell patch-clamp a nd field excitatory postsynaptic potential (fEPSP) recording technique s, we examined the groups of mGluRs that act as autoreceptors at later al and medial perforant path synapses in adult rat hippocampal slices. 2. Consistent with previous reports, the group III mGluR agonist (D,L )-2-amino-4-phosphonobutyric acid reduced fEPSPs and excitatory postsy naptic currents (EPSCs) in the dentate gyrus. However, the group-II-se lective agonist (2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl) glycine (DCG-IV) also reduced fEPSPs and EPSCs, suggesting that multiple mGluR subtypes may serve as autoreceptors at perforant path synapses. 3. Se lective activation of either medial or lateral perforant pathways reve aled that micromolar concentrations of (L)-2-amino-4-phosphonobutyric acid (L-AP4) reduce fEPSPs in lateral but not medial perforant path, s uggesting group III involvement at the lateral perforant pathway. Conv ersely, DCG-IV and 2R,4R-4-aminopynolidine-2,4-dicarboxylate, another group-II-selective mGluR agonist, potently reduced fEPSPs at the media l but not lateral perforant path, suggesting that a group II mGluR may act as an autoreceptor at the medial perforant path-dentate gyrus syn apse. 4. Antagonist studies with group-selective antagonists such as ( 2S,3S,4S)-2-methyl-2-(carboxycyclpropyl)glycine (MCCG; group II) and a lpha-methyl-L-AP4 (MAP4; group III) suggest differential involvement o f each group at these synapses. The effect of L AP4 at the lateral per forant path synapse was blocked by MAP-4, but not MCCG. In contrast, t he effect of DCG-IV was blocked by application of MCCG, but not MAP4. 5. Previous studies suggest that the effect of L-AP4 at the lateral pe rforant path synapse is mediated by a presynaptic mechanism. In the pr esent studies, we found that concentrations of DCG-IV that reduce tran smission at the medial perforant path synapse reduce paired-pulse depr ession and do not reduce kainate-evoked currents recorded from dentate granule cells. This is consistent with the hypothesis that DCG-IV als o acts by a presynaptic mechanism.